Alkyne compounds with MCH antagonistic activity and medicaments comprising these compounds

ABSTRACT

The present invention relates to alkyne compounds of general formula I 
                         
wherein the groups and residues A, B, W, X, Y, Z, R 1  and R 2  have the meanings given in claim  1 . The invention further relates to pharmaceutical compositions containing at least one alkyne according to the invention. In view of their MCH-receptor antagonistic activity the pharmaceutical compositions according to the invention are suitable for the treatment of metabolic disorders and/or eating disorders, particularly obesity, bulimia, anorexia, hyperphagia and diabetes.

The present invention relates to new alkyne compounds, thephysiologically acceptable salts thereof as well as their use as MCHantagonists and their use in preparing a pharmaceutical preparationwhich is suitable for the prevention and/or treatment of symptoms and/ordiseases caused by MCH or causally connected with MCH in some other way.The invention also relates to the use of a compound according to theinvention for influencing eating behaviour and for reducing body weightand/or for preventing any increase in body weight in a mammal. Itfurther relates to compositions and medicaments containing a compoundaccording to the invention and processes for preparing them.

BACKGROUND TO THE INVENTION

The intake of food and its conversion in the body is an essential partof life for all living creatures. Therefore, deviations in the intakeand conversion of food generally lead to problems and also illness. Thechanges in the lifestyle and nutrition of humans, particularly inindustrialised countries, have promoted obesity in recent decades. Inaffected people, obesity leads directly to restricted mobility and areduction in the quality of life. There is the additional factor thatobesity often leads to other diseases such as, for example, diabetes,dyslipidaemia, high blood pressure, arteriosclerosis and coronary heartdisease. Moreover, high body weight alone puts an increased strain onthe support and mobility apparatus, which can lead to chronic pain anddiseases such as arthritis or osteoarthritis. Thus, obesity is a serioushealth problem for society.

The term obesity means an excess of adipose tissue. In this connection,obesity is fundamentally to be seen as the increased level of fatnesswhich leads to a health risk. In the last analysis it is not preciselypossible to draw a distinction between normal individuals and thosesuffering from obesity, but the health risk accompanying obesity ispresumed to rise continuously as the level of fatness increases. Forsimplicity's sake, in the present invention, individuals with a BodyMass Index (BMI), which is defined as the body weight measured inkilograms divided by the height (in metres) squared, above a value of 25and more particularly above 30 are preferably regarded as suffering fromobesity.

Apart from physical activity and a change in nutrition, there iscurrently no convincing treatment option for effectively reducing bodyweight. However, as obesity is a major risk factor in the development ofserious and even life-threatening diseases, it is all the more importantto have access to pharmaceutical active substances for the preventionand/or treatment of obesity. One approach which has been proposed veryrecently is the therapeutic use of MCH antagonists (cf. inter alia WO01/21577, WO 01/82925).

Melanin-concentrating hormone (MCH) is a cyclic neuropeptide consistingof 19 amino acids. It is synthesised predominantly in the hypothalamusin mammals and from there travels to other parts of the brain by theprojections of hypothalamic neurones. Its biological activity ismediated in humans through two different G-protein-coupled receptors(GPCRs) from the family of rhodopsin-related GPCRs, namely the MCHreceptors 1 and 2 (MCH-1R, MCH-2R).

Investigations into the function of MCH in animal models have providedgood indications for a role of the peptide in regulating the energybalance, i.e. changing metabolic activity and food intake [1,2]. Forexample, after intraventricular administration of MCH in rats, foodintake was increased compared with control animals. Additionally,transgenic rats which produce more MCH than control animals, when givena high-fat diet, responded by gaining significantly more weight thananimals without an experimentally altered MCH level. It was also foundthat there is a positive correlation between phases of increased desirefor food and the quantity of MCH mRNA in the hypothalamus of rats.However, experiments with MCH knock-out mice are particularly importantin showing the function of MCH. Loss of the neuropeptide results in leananimals with a reduced fat mass, which take in significantly less foodthan control animals.

The anorectic effects of MCH are mediated in rodents through theG_(∀s)-coupled MCH-1R [3-6]. Unlike primates, ferrets and dogs, nosecond receptor has hitherto been found in rodents. After losing theMCH-1R, knock-out mice have a lower fat mass, an increased energyconversion and, when fed on a high fat diet, do not put on weight,compared with control animals. Another indication of the importance ofthe MCH-MCH-1R system in regulating the energy balance results fromexperiments with a receptor antagonist (SNAP-7941) [3]. In long termtrials the animals treated with the antagonist lose significant amountsof weight.

In addition to its anorectic effect, the MCH-1R antagonist SNAP-7941also achieves additional anxiolytic and antidepressant effects inbehavioural experiments on rats [3]. Thus, there are clear indicationsthat the MCH-MCH-1R system is involved not only in regulating the energybalance but also in affectivity.

Literature:

-   1. Qu, D., et al., A role for melanin-concentrating hormone in the    central regulation of feeding behaviour. Nature, 1996. 380(6571): p.    243-7.-   2. Shimada, M., et al., Mice lacking melanin-concentrating hormone    are hypophagic and lean. Nature, 1998. 396(6712): p. 670-4.-   3. Borowsky, B., et al., Antidepressant, anxiolytic and anorectic    effects of a melanin-concentrating hormone-1 receptor antagonist.    Nat Med, 2002. 8(8): p. 825-30.-   4. Chen, Y., et al., Targeted disruption of the    melanin-concentrating hormone receptor-1 results in hyperphagia and    resistance to diet-induced obesity. Endocrinology, 2002. 143(7): p.    2469-77.-   5. Marsh, D. J., et al., Melanin-concentrating hormone 1    receptor-deficient mice are lean, hyperactive, and hyperphagic and    have altered metabolism. Proc Natl Acad Sci U S A, 2002. 99(5): p.    3240-5.-   6. Takekawa, S., et al., T-226296: A novel, orally active and    selective melanin-concentrating hormone receptor antagonist. Eur J    Pharmacol, 2002. 438(3): p.129-35.

In the patent literature certain amine compounds are proposed as MCHantagonists. Thus, WO 01/21577 (Takeda) describes compounds of formula

wherein Ar¹ denotes a cyclic group, X denotes a spacer, Y denotes a bondor a spacer, Ar denotes an aromatic ring which may be fused with anon-aromatic ring, R¹ and R² independently of one another denote H or ahydrocarbon group, while R¹ and R² together with the adjacent N atom mayform an N-containing hetero ring and R² with Ar may also form aspirocyclic ring, R together with the adjacent N atom and Y may form anN-containing hetero ring, as MCH antagonists for the treatment ofobesity.

Moreover WO 01/82925 (Takeda) also describes compounds of formula

wherein Ar¹ denotes a cyclic group, X and Y represent spacer groups, Ardenotes an optionally substituted fused polycyclic aromatic ring, R¹ andR² independently of one another represent H or a hydrocarbon group,while R¹ and R² together with the adjacent N atom may form anN-containing heterocyclic ring and R² together with the adjacent N atomand Y may form an N-containing hetero ring, as MCH antagonists for thetreatment of obesity, inter alia.

AIM OF THE INVENTION

The aim of the present invention is to discover new alkyne compounds,particularly those which have an activity as MCH antagonists.

A further aim of the invention is to provide new alkyne compounds whichmake it possible to influence the eating behaviour of mammals and inparticular achieve a reduction in body weight and/or prevent an increasein body weight in mammals.

The present invention further sets out to provide new pharmaceuticalcompositions which are suitable for the prevention and/or treatment ofsymptoms and/or diseases caused by MCH or otherwise causally connectedto MCH. In particular, the aim of this invention is to providepharmaceutical compositions for the treatment of metabolic disorderssuch as obesity and/or diabetes as well as diseases and/or disorderswhich are associated with obesity and diabetes. Other objectives of thepresent invention are concerned with demonstrating advantageous uses ofthe compounds according to the invention. The invention also sets out toprovide a process for preparing the alkyne compounds according to theinvention. Other aims of the present invention will be immediatelyapparent to the skilled man from the foregoing remarks and those thatfollow.

SUBJECT MATTER OF THE INVENTION

A first object of the present invention comprises alkyne compounds ofgeneral formula I

wherein

-   R¹, R² independently of one another denote H, a C₁₋₈-alkyl or    C₃₋₇-cycloalkyl group optionally substituted by the group R¹¹, while    a —CH₂— group in position 3 or 4 of a 5-, 6- or 7-membered    cycloalkyl group may be replaced by —O—, —S— or —NR¹³—, or a phenyl    or pyridinyl group optionally mono- or polysubstituted by the group    R¹² and/or monosubstituted by nitro, or    -   R¹ and R² form a C₂₋₈-alkylene bridge wherein        -   one or two —CH₂— groups may be replaced independently of one            another by —O—, —S—, —SO—, —(SO₂)—, —C═N—R¹⁸—, —C═N—O—R¹⁸—,            —CO—, —C(═CH₂)— or —NR¹³— in such a way that heteroatoms are            not directly connected to one another,    -   while in the above-defined alkylene bridge one or more H atoms        may be replaced by R¹⁴, and    -   while the above-defined alkylene bridge may be substituted by        one or two identical or different carbo- or heterocyclic groups        Cy in such a way that the bond between the alkylene bridge and        the group Cy is formed        -   via a single or double bond,        -   via a common C atom forming a spirocyclic ring system,        -   via two common, adjacent C and/or N atoms forming a fused            bicyclic ring system or        -   via three or more C and/or N atoms forming a bridged ring            system,-   X denotes a single bond or a C₁₋₆-alkylene bridge wherein    -   a —CH₂— group may be replaced by —CH═CH— or —C≡C— and/or    -   one or two —CH₂— groups may be replaced independently of one        another by —O—, —S—, —(SO)—, —(SO₂)—, —CO— or —NR⁴— in such a        way that in each case two O, S or N atoms or an O and an S atom        are not directly connected to one another,    -   while the bridge X may be attached to R¹ including the N atom        attached to R¹ and X forming a heterocyclic group, while the        bridge X may additionally also be attached to R², including the        N-atom attached to R² and X, forming a heterocyclic group, and    -   two C atoms or one C and one N atom of the alkylene bridge may        be joined together by an additional C₁₋₄-alkylene bridge, and    -   a C atom may be substituted by R¹⁰ and/or one or two C atoms in        each case may be substituted with one or two identical or        different substituents selected from C₁₋₆-alkyl, C₂₋₆-alkenyl,        C₂₋₆-alkynyl, C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₃-alkyl,        C₄₋₇-cycloalkenyl and C₄₋₇-cycloalkenyl-C₁₋₃-alkyl, while two        alkyl and/or alkenyl substituents may be joined together,        forming a carbocyclic ring system, and-   W, Z independently of one another denote a single bond or a    C₁₋₄-alkylene bridge,    -   while in the group W and/or Z a —CH₂— group not adjacent to the        —C≡C— group may be replaced by —O— or —NR⁵—, and    -   two adjacent C atoms or one C atom and an adjacent N atom may be        joined together by an additional C₁₋₄-alkylene bridge, and    -   in the alkylene bridge and/or in the additional alkylene bridge        a C atom may be substituted by R¹⁰ and/or one or two C atoms        independently of one another may be substituted by one or two        identical or different C₁₋₆-alkyl groups, while two alkyl groups        may be joined together, forming a carbocyclic ring, and-   Y denotes one of the meanings given for Cy,    -   while R¹ may be attached to Y including the group X and the N        atom attached to R¹ and X, forming a heterocyclic group fused to        Y, and/or    -   X may be attached to Y forming a carbo- or heterocyclic group        fused to Y, and-   A denotes one of the meanings given for Cy and-   B denotes one of the meanings given for Cy or    -   C₁₋₆-alkyl, C₁₋₆-alkenyl, C₁₋₆-alkynyl,        C₃₋₇-cycloalkyl-C₁₋₃-alkyl, C₃₋₇-cycloalkenyl-C₁₋₃-alkyl,        C₃₋₇-cycloalkyl-C₁₋₃-alkenyl or C₃₋₇-cycloalkyl-C₁₋₃-alkynyl,        wherein one or more C atoms may be mono- or polysubstituted by        halogen and/or may be monosubstituted by hydroxy or cyano and/or        cyclic groups may be mono- or polysubstituted by R²⁰,-   Cy denotes a carbo- or heterocyclic group selected from one of the    following meanings    -   a saturated 3- to 7-membered carbocyclic group,    -   an unsaturated 4- to 7-membered carbocyclic group,    -   a phenyl group,    -   a saturated 4- to 7-membered or unsaturated 5- to 7-membered        heterocyclic group with an N, O or S atom as heteroatom,    -   a saturated or unsaturated 5- to 7-membered heterocyclic group        with two or more N atoms or with one or two N atoms and an O or        S atom as heteroatoms,    -   an aromatic heterocyclic 5- or 6-membered group with one or more        identical or different heteroatoms selected from N, O and/or S,    -   while the above-mentioned 4-, 5-, 6- or 7-membered groups may be        attached via two common, adjacent C atoms fused to a phenyl or        pyridine ring, and    -   in the above-mentioned 5-, 6- or 7-membered groups one or two        non-adjacent —CH₂— groups may be replaced independently of one        another by a —CO—, —C(═CH₂)—, —(SO)— or —(SO₂)— group, and    -   the above-mentioned saturated 6- or 7-membered groups may also        be present as bridged ring systems with an imino,        (C₁₋₄-alkyl)-imino, methylene, (C₁₋₄-alkyl)-methylene or        di-(C₁₋₄-alkyl)-methylene bridge, and    -   the above-mentioned cyclic groups may be mono- or        polysubstituted at one or more C atoms with R²⁰, in the case of        a phenyl group they may also additionally be monosubstituted        with nitro, and/or one or more NH groups may be substituted with        R²¹,-   R⁴, R⁵ independently of one another have one of the meanings given    for R¹⁷,-   R¹⁰ denotes hydroxy, ω-hydroxy-C₁₋₃-alkyl, C₁₋₄-alkoxy,    ω-(C₁₋₄-alkoxy)-C₁₋₃-alkyl, carboxy, C₁₋₄-alkoxycarbonyl, amino,    C₁₋₄-alkyl-amino, di-(C₁₋₄-alkyl)-amino, cyclo-C₃₋₆-alkyleneimino,    amino-C₁₋₃-alkyl, C₁₋₄-alkyl-amino-C₁₋₃-alkyl,    di-(C₁₋₄-alkyl)-amino-C₁₋₃-alkyl,    cyclo-C₃₋₆-alkyleneimino-C₁₋₃-alkyl, amino-C₂₋₃-alkoxy,    C₁₋₄-alkyl-amino-C₂₋₃-alkoxy, di-(C₁₋₄-alkyl)-amino-C₂₋₃-alkoxy,    cyclo-C₃₋₆-alkyleneimino-C₂₋₃-alkoxy, aminocarbonyl,    C₁₋₄-alkyl-aminocarbonyl, di-(C₁₋₄-alkyl)-aminocarbonyl,    cyclo-C₃₋₆-alkyleneimino-carbonyl,-   R¹¹ denotes C₂₋₆-alkenyl, C₂₋₆-alkynyl, R¹⁵—O, R¹⁵—O—CO, R¹⁵—CO—O,    R¹⁶R¹⁷N, R¹⁸R¹⁹N—CO or Cy,-   R¹² has one of the meanings given for R²⁰,-   R¹³ has one of the meanings given for R¹⁷, with the exception of    carboxy,-   R¹⁴ denotes halogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, R¹⁵—O,    R¹⁵—O—CO, R¹⁵—CO, R¹⁵—CO—O, R¹⁶R¹⁷N, R¹⁸R¹⁹N—CO, R¹⁵—O—C₁₋₃-alkyl,    R¹⁵—O—CO—C₁₋₃-alkyl, R¹⁵—O—CO—NH, R¹⁵—SO₂—NH,    R¹⁵—O—CO—NH—C₁₋₃-alkyl, R¹⁵—SO₂—NH—C₁₋₃-alkyl, R¹⁵—CO—C₁₋₃-alkyl,    R¹⁵—CO—O—C₁₋₃-alkyl, R¹⁶R¹⁷N—C₁₋₃-alkyl, R¹⁸R¹⁹N—CO—C₁₋₃-alkyl or    Cy-C₁₋₃-alkyl,-   R¹⁵ denotes H, C₁₋₄-alkyl, C₃₋₇-cycloalkyl,    C₃₋₇-cycloalkyl-C₁₋₃-alkyl, phenyl, phenyl-C₁₋₃-alkyl, pyridinyl or    pyridinyl-C₁₋₃-alkyl,-   R¹⁶ denotes H, C₁₋₆-alkyl, C₃₋₇-cycloalkyl,    C₃₋₇-cycloalkyl-C₁₋₃-alkyl, C₄₋₇-cycloalkenyl,    C₄₋₇-cycloalkenyl-C₁₋₃-alkyl, ω-hydroxy-C₂₋₃-alkyl,    ω-(C₁₋₄-alkoxy)-C₂₋₃-alkyl, amino-C₂₋₆-alkyl,    C₁₋₄-alkyl-amino-C₂₋₆-alkyl, di-(C₁₋₄-alkyl)-amino-C₂₋₆-alkyl or    cyclo-C₃₋₆-alkyleneimino-C₂₋₆-alkyl,-   R¹⁷ has one of the meanings given for R¹⁶ or denotes phenyl,    phenyl-C₁₋₃-alkyl, pyridinyl, dioxolan-2-yl, —CHO,    C₁₋₄-alkylcarbonyl, carboxy, hydroxycarbonyl-C₁₋₃-alkyl,    C₁₋₄-alkoxycarbonyl, C₁₋₄-alkoxycarbonyl-C₁₋₃-alkyl,    C₁₋₄-alkylcarbonylamino-C₂₋₃-alkyl,    N-(C₁₋₄-alkylcarbonyl)-N-(C₁₋₄-alkyl)-amino-C₂₋₃-alkyl,    C₁₋₄-alkylsulphonyl, C₁₋₄-alkylsulphonylamino-C₂₋₃-alkyl or    N-(C₁₋₄-alkylsulphonyl)-N-(C₁₋₄-alkyl)-amino-C₂₋₃-alkyl-   R¹⁸, R¹⁹ independently of one another denote H or C₁₋₆-alkyl,-   R²⁰ denotes halogen, hydroxy, cyano, C₁₋₆-alkyl, C₂₋₆-alkenyl,    C₂₋₆-alkynyl, C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₃-alkyl,    hydroxy-C₁₋₃-alkyl, R²²—C₁₋₃-alkyl or has one of the meanings given    for R²²,-   R²¹ denotes C₁₋₄-alkyl, ω-hydroxy-C₂₋₆-alkyl,    ω-C₁₋₄-alkoxy-C₂₋₆-alkyl, ω-C₁₋₄-alkyl-amino-C₂₋₆-alkyl,    ω-di-(C₁₋₄-alkyl)-amino-C₂₋₆-alkyl,    ω-cyclo-C₃₋₆-alkyleneimino-C₂₋₆-alkyl, phenyl, phenyl-C₁₋₃-alkyl,    C₁₋₄-alkyl-carbonyl, C₁₋₄-alkoxy-carbonyl, C₁₋₄-alkylsulphonyl,    phenylcarbonyl or phenyl-C₁₋₃-alkyl-carbonyl,-   R²² denotes pyridinyl, phenyl, phenyl-C₁₋₃-alkoxy, OHC, HO—N═HC,    C₁₋₄-alkoxy-N═HC, C₁₋₄-alkoxy, C₁₋₄-alkylthio, carboxy,    C₁₋₄-alkylcarbonyl, C₁₋₄-alkoxycarbonyl, aminocarbonyl,    C₁₋₄-alkylamino-carbonyl, di-(C₁₋₄-alkyl)-aminocarbonyl,    cyclo-C₃₋₆-alkyl-amino-carbonyl, cyclo-C₃₋₆-alkyleneimino-carbonyl,    cyclo-C₃₋₆-alkyleneimino-C₂₋₄-alkyl-aminocarbonyl,    C₁₋₄-alkyl-sulphonyl, C₁₋₄-alkyl-sulphinyl,    C₁₋₄-alkyl-sulphonylamino, amino, C₁₋₄-alkylamino,    di-(C₁₋₄-alkyl)-amino, C₁₋₄-alkyl-carbonyl-amino,    cyclo-C₃₋₆-alkyleneimino, phenyl-C₁₋₃-alkylamino,    N-(C₁₋₄-alkyl)-phenyl-C₁₋₃-alkylamino, acetylamino, propionylamino,    phenylcarbonyl, phenylcarbonylamino, phenylcarbonylmethylamino,    hydroxy-C₂₋₃-alkylaminocarbonyl, (4-morpholinyl)carbonyl,    (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl,    (hexahydro-1-azepinyl)carbonyl, (4-methyl-1-piperazinyl)carbonyl,    methylenedioxy, aminocarbonylamino or alkylaminocarbonylamino,

while in the above-mentioned groups and residues, particularly in A, B,W, X, Y, Z, R¹ to R⁵ and R¹⁰ to R²², in each case one or more C atomsmay additionally be mono- or polysubstituted by F and/or in each caseone or two C atoms independently of one another may additionally bemonosubstituted by Cl or Br and/or in each case one or more phenyl ringsindependently of one another additionally have one, two or threesubstituents selected from among F, Cl, Br, I, cyano, C₁₋₄-alkyl,C₁₋₄-alkoxy, difluoromethyl, trifluoromethyl, hydroxy, amino,C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, acetylamino, aminocarbonyl,difluoromethoxy, trifluoromethoxy, amino-C₁₋₃-alkyl,C₁₋₃-alkylamino-C₁₋₃-alkyl- and di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl- and/ormay be monosubstituted by nitro, and

the H atom of any carboxy group present or an H atom bound to an N atommay each be replaced by a group which can be cleaved in vivo,

the tautomers, the diastereomers, the enantiomers, the mixtures thereofand the salts thereof.

The invention also relates to the compounds in the form of theindividual optical isomers, mixtures of the individual enantiomers orracemates, in the form of the tautomers and in the form of the freebases or the corresponding acid addition salts with pharmacologicallysafe acids. The subject of the invention also includes the compoundsaccording to the invention, including the salts thereof, wherein one ormore hydrogen atoms are replaced by deuterium.

This invention also includes the physiologically acceptable salts of thealkyne compounds according to the invention as described above andhereinafter.

This invention also relates to compositions containing at least onealkyne compound according to the invention and/or a salt according tothe invention optionally together with one or more physiologicallyacceptable excipients.

Also covered by this invention are pharmaceutical compositionscontaining at least one alkyne compound according to the inventionand/or a salt according to the invention optionally together with one ormore inert carriers and/or diluents.

This invention also relates to the use of at least one alkyne compoundaccording to the invention and/or a salt according to the invention forinfluencing the eating behaviour of a mammal.

The invention further relates to the use of at least one alkyne compoundaccording to the invention and/or a salt according to the invention forreducing the body weight and/or for preventing an increase in the bodyweight of a mammal.

The invention also relates to the use of at least one alkyne compoundaccording to the invention and/or a salt according to the invention forpreparing a pharmaceutical composition with an MCH receptor-antagonisticactivity, particularly with an MCH-1 receptor-antagonistic activity.

This invention also relates to the use of at least one alkyne compoundaccording to the invention and/or a salt according to the invention forpreparing a pharmaceutical composition which is suitable for theprevention and/or treatment of symptoms and/or diseases which are causedby MCH or are otherwise causally connected with MCH.

A further object of this invention is the use of at least one alkynecompound according to the invention and/or a salt according to theinvention for preparing a pharmaceutical composition which is suitablefor the prevention and/or treatment of metabolic disorders and/or eatingdisorders, particularly obesity, bulimia, bulimia nervosa, cachexia,anorexia, anorexia nervosa and hyperphagia

The invention also relates to the use of at least one alkyne compoundaccording to the invention and/or a salt according to the invention forpreparing a pharmaceutical composition which is suitable for theprevention and/or treatment of diseases and/or disorders associated withobesity, particularly diabetes, especially type II diabetes,complications of diabetes including diabetic retinopathy, diabeticneuropathy, diabetic nephropathy, insulin resistance, pathologicalglucose tolerance, encephalorrhagia, cardiac insufficiency,cardiovascular diseases, particularly arteriosclerosis and high bloodpressure, arthritis and gonitis.

In addition the present invention relates to the use of at least onealkyne compound according to the invention and/or a salt according tothe invention for preparing a pharmaceutical composition which issuitable for the prevention and/or treatment of hyperlipidaemia,cellulitis, fat accumulation, malignant mastocytosis, systemicmastocytosis, emotional disorders, affective disorders, depression,anxiety, sleep disorders, reproductive disorders, sexual disorders,memory disorders, epilepsy, forms of dementia and hormonal disorders.

The invention also relates to the use of at least one alkyne compoundaccording to the invention and/or a salt according to the invention forpreparing a pharmaceutical composition which is suitable for theprevention and/or treatment of urinary problems, such as for exampleurinary incontinence, overactive bladder, urgency, nycturia andenuresis.

The invention further relates to processes for preparing for preparing apharmaceutical composition according to the invention, characterised inthat at least one alkyne compound according to the invention and/or asalt according to the invention is incorporated in one or more inertcarriers and/or diluents by a non-chemical method.

The invention also relates to a pharmaceutical composition containing afirst active substance which is selected from the alkyne compoundsaccording to the invention and/or the corresponding salts as well as asecond active substance which is selected from the group consisting ofactive substances for the treatment of diabetes, active substances forthe treatment of diabetic complications, active substances for thetreatment of obesity, preferably other than MCH antagonists, activesubstances for the treatment of high blood pressure, active substancesfor the treatment of hyperlipidaemia, including arteriosclerosis, activesubstances for the treatment of arthritis, active substances for thetreatment of anxiety states and active substances for the treatment ofdepression, optionally together with one or more inert carriers and/ordiluents.

This invention further relates to a process for preparing alkynecompounds of formula A.5R¹R²N—X—Y—C≡C—W-A-B  (A.5)

while in formulae A.1, A.2, A.3, A.4 and A.5 R¹, R², X, Y, W, A and Bhave one of the meanings given hereinbefore and hereinafter and Ydenotes aryl or heteroaryl,

wherein a halogen compound of formula A.1HO—X—Y-Hal  (A.1)

wherein Hal denotes chlorine, bromine or iodine, preferably bromine oriodine,

is reacted with an alkyne compound of formula A.2H—C≡C—W-A-B  (A.2)

in the presence of a suitable palladium catalyst, a suitable base andcopper(I)iodide in a suitable solvent, and

the resulting compound of formula A.3HO—X—Y—C≡C—W-A-B  (A.3)

is reacted with methanesulphonic acid chloride (MsCl) to form themethanesulphonate derivative A.4,MsO—X—Y—C≡C—W-A-B  (A.4)

which is further reacted with an amine of formula H—NR¹R² to obtain theend product A.5.

This invention further relates to a process for preparing alkynecompounds of formula B.5R¹R²N—X—Y-Z-C≡C-A-B  (B.5)

while in formulae B.1, B.2, B.3, B.4 and B.5 R¹, R², X, Y, Z, A and Bhave one of the meanings given hereinbefore and hereinafter and Aparticularly denotes aryl or heteroaryl,

wherein a halogen compound of formula B.1Hal-A-B  (B.1)

wherein Hal denotes chlorine, bromine or iodine, preferably bromine oriodine,

is reacted with an alkyne compound of formula B.2HO—X—Y-Z-C≡C—H  (B.2)

in the presence of a suitable palladium catalyst, a suitable base andcopper(I)iodide in a suitable solvent, and

the resulting compound of formula B.3HO—X—Y-Z-C≡C-A-B  (B.3)

is reacted with methanesulphonic acid chloride (MsCl) to form themethanesulphonate derivative B.4,MsO—X—Y-Z-C≡C-A-B  (B.4)

which is further reacted with an amine of formula H—NR¹R² to obtain theend product B.5.

Moreover this invention relates to a process for preparing alkynecompounds of formula C.3R¹R²N—X—Y—C≡C—W-A-B  (C.3)

while in formulae C.1, C.2 and C.3 R¹, R², X, Y, W, A and B have one ofthe meanings given hereinbefore and hereinafter and Y denotes aryl orheteroaryl,

wherein a halogen compound of formula C.1R¹R²N—X—Y-Hal  (C.1)

wherein Hal denotes chlorine, bromine or iodine, preferably bromine oriodine,

is further reacted with an alkyne compound of formula C.2H—C≡C—W-A-B  (C.2)

in the presence of a suitable palladium catalyst, a suitable base andcopper(I)iodide in a suitable solvent to obtain the end product C.3.

This invention further relates to a process for preparing alkynecompounds of formula D.3R¹R²N—X—Y-Z-C≡C-A-B  (D.3)

while in formulae D.1, D.2 and D.3 R¹, R², X, Y, Z, A and B have one ofthe meanings given hereinbefore and hereinafter and A particularlydenotes aryl or heteroaryl,

wherein a halogen compound of formula D.2Hal-A-B  (D.2)

wherein Hal denotes chlorine, bromine or iodine, preferably bromine oriodine,

is reacted with an alkyne compound of formula D.1R¹R²N—X—Y-Z-C≡C—H  (D.1)

in the presence of a suitable palladium catalyst, a suitable base andcopper(I)iodide in a suitable solvent to obtain the end product D.3.

MORE DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise specified the groups, residues and substituents,particularly A, B, W, X, Y, Z, R¹ to R⁵ and R¹⁰ to R²², have themeanings given hereinbefore and hereinafter.

According to one embodiment of the invention the groups R¹, R², X, W, Z,B, R¹⁰, R¹³, R¹⁴, R¹⁵, R¹⁷, R²⁰, R²² have the following meanings:

-   R¹, R² independently of one another denote H, a C₁₋₈-alkyl or    C₃₋₇-cycloalkyl group optionally substituted by the group R¹¹ or a    phenyl group optionally mono- or polysubstituted by the group R¹²    and/or monosubstituted by nitro, or    -   R¹ and R² form a C₂₋₈-alkylene bridge, wherein        -   one or two —CH₂— groups independently of one another may be            replaced by —CH═N— or —CH═CH— and/or        -   one or two —CH₂— groups independently of one another may be            replaced by —O—, —S—, —CO—, —C(═CH₂)— or —NR¹³— such a way            that heteroatoms are not directly joined together,    -   while in the alkylene bridge defined hereinbefore one or more H        atoms may be replaced by R¹⁴, and    -   the alkylene bridge defined hereinbefore may be substituted by        one or two identical or different carbo- or heterocyclic groups        Cy in such a way that the bond between the alkylene bridge and        the group Cy is made        -   via a single or double bond,        -   via a common C atom forming a spirocyclic ring system,        -   via two common adjacent C- and/or N atoms forming a fused            bicyclic ring system or        -   via three or more C- and/or N atoms forming a bridged ring            system,-   X denotes a single bond or a C₁₋₆-alkylene bridge, wherein    -   a —CH₂— group may be replaced by —CH═CH— or —C≡C— and/or    -   one or two —CH₂— groups independently of one another may be        replaced by —O—, —S—, —(SO)—, —(SO₂)—, —CO— or —NR⁴— in such a        way that in each case two O, S or N atoms or an O and an S atom        are not directly joined together,    -   while the bridge X may be attached to R¹ including the N atom        attached to R¹ and X, forming a heterocyclic group, and    -   while two C atoms or a C and an N atom of the alkylene bridge        may be joined together by an additional C₁₋₄-alkylene bridge,        and    -   a C atom may be substituted by R¹⁰ and/or one or two C atoms in        each case may be substituted by one or two identical or        different C₁₋₆-alkyl groups, and-   W, Z independently of one another denote a single bond or a    C₁₋₄-alkylene bridge,    -   while in the group W and/or Z a —CH₂— group not adjacent to the        —C≡C— group may be replaced by —O— or —NR⁵—, and    -   two adjacent C atoms or a C atom and an adjacent N atom may be        joined together by an additional C₁₋₄-alkylene bridge, and    -   in the alkylene bridge and/or in the additional alkylene bridge        a C atom may be substituted by R¹⁰ and/or one or two C atoms        independently of one another may be substituted by one or two        identical or different C₁₋₆-alkyl groups, and-   B has one of the meanings given for Cy or    -   denotes C₁₋₆-alkyl, C₁₋₆-alkenyl, C₁₋₆-alkynyl,        C₃₋₇-cycloalkyl-C₁₋₃-alkyl, C₃₋₇-cycloalkenyl-C₁₋₃-alkyl,        C₃₋₇-cycloalkyl-C₁₋₃-alkenyl or C₃₋₇-cycloalkyl-C₁₋₃-alkynyl,        wherein one or more C atoms may be mono- or polysubstituted by        fluorine and cyclic groups may be mono- or polysubstituted by        R²⁰,-   R¹⁰ denotes hydroxy, ω-hydroxy-C₁₋₃-alkyl, C₁₋₄-alkoxy,    ω-(C₁₋₄-alkoxy)-C₁₋₃-alkyl, amino, C₁₋₄-alkyl-amino,    di-(C₁₋₄-alkyl)-amino, cyclo-C₃₋₆-alkyleneimino, amino-C₁₋₃-alkyl,    C₁₋₄-alkyl-amino-C₁₋₃-alkyl, di-(C₁₋₄-alkyl)-amino-C₁₋₃-alkyl,    cyclo-C₃₋₆-alkyleneimino-C₁₋₃-alkyl, amino-C₂₋₃-alkoxy,    C₁₋₄-alkyl-amino-C₂₋₃-alkoxy, di-(C₁₋₄-alkyl)-amino-C₂₋₃-alkoxy or    cyclo-C₃₋₆-alkyleneimino-C₂₋₃-alkoxy,-   R¹³ has one of the meanings given for R¹⁷,-   R¹⁴ denotes halogen, C₁₋₆-alkyl, R¹⁵—O, R¹⁵—O—CO, R¹⁵—CO, R¹⁵—CO—O,    R¹⁶R¹⁷N, R¹⁸R¹⁹N—CO, R¹⁵—O—C₁₋₃-alkyl, R¹⁵—O—CO—C₁₋₃-alkyl,    R¹⁵—CO—C₁₋₃-alkyl, R¹⁵—CO—O—C₁₋₃-alkyl, R¹⁶R¹⁷N—C₁₋₃-alkyl,    R¹⁸R¹⁹N—CO—C₁₋₃-alkyl or Cy-C₁₋₃-alkyl,-   R¹⁵ denotes H, C₁₋₄-alkyl, C₃₋₇-cycloalkyl,    C₃₋₇-cycloalkyl-C₁₋₃-alkyl, phenyl or phenyl-C₁₋₃-alkyl,-   R¹⁷ has one of the meanings given for R¹⁶ or denotes phenyl,    phenyl-C₁₋₃-alkyl, C₁₋₄-alkylcarbonyl, hydroxycarbonyl-C₁₋₃-alkyl,    C₁₋₄-alkylcarbonylamino-C₂₋₃-alkyl,    N-(C₁₋₄-alkylcarbonyl)-N-(C₁₋₄-alkyl)-amino-C₂₋₃-alkyl,    C₁₋₄-alkylsulphonyl, C₁₋₄-alkylsulphonylamino-C₂₋₃-alkyl or    N-(C₁₋₄-alkylsulphonyl)-N(-C₁₋₄-alkyl)-amino-C₂₋₃-alkyl-   R²⁰ denotes halogen, hydroxy, cyano, C₁₋₆-alkyl, C₃₋₇-cycloalkyl,    C₃₋₇-cycloalkyl-C₁₋₃-alkyl, hydroxy-C₁₋₃-alkyl, R²²—C₁₋₃-alkyl or    has one of the meanings given for R²²,-   R²² denotes phenyl, phenyl-C₁₋₃-alkoxy, C₁₋₄-alkoxy, C₁₋₄-alkylthio,    carboxy, C₁₋₄-alkylcarbonyl, C₁₋₄-alkoxycarbonyl, aminocarbonyl,    C₁₋₄-alkylaminocarbonyl, di-(C₁₋₄-alkyl)-aminocarbonyl,    cyclo-C₃₋₆-alkyleneimino-carbonyl, C₁₋₄-alkyl-sulphonyl,    C₁₋₄-alkyl-sulphinyl, C₁₋₄-alkyl-sulphonylamino, amino,    C₁₋₄-alkylamino, di-(C₁₋₄-alkyl)-amino, cyclo-C₃₋₆-alkyleneimino,    phenyl-C₁₋₃-alkylamino, N-(C₁₋₄-alkyl)-phenyl-C₁₋₃-alkylamino,    acetylamino, propionylamino, phenylcarbonyl, phenylcarbonylamino,    phenylcarbonylmethylamino, hydroxyalkylaminocarbonyl,    (4-morpholinyl)carbonyl, (1-pyrrolidinyl)carbonyl,    (1-piperidinyl)carbonyl, (hexahydro-1-azepinyl)carbonyl,    (4-methyl-1-piperazinyl)carbonyl, methylenedioxy, aminocarbonylamino    or alkylaminocarbonylamino,

while R⁴, R¹¹, R¹², R¹⁶, R¹⁸, R¹⁹ and Cy are as hereinbefore defined.

If R¹ and R² are not joined together via an alkylene bridge, R¹ and R²independently of one another preferably denote a C₁₋₈-alkyl orC₃₋₇-cycloalkyl group optionally substituted by the group R¹¹, while a—CH₂— group in position 3 or 4 of a 5-, 6- or 7-membered cycloalkylgroup may be replaced by —O—, —S— or —NH—, —N(C₁₋₄-alkyl)- or—N(CO—O—C₁₋₄-alkyl)-, or phenyl or pyridinyl group optionally mono- orpolysubstituted by the group R¹² and/or monosubstituted by nitro, andone of the groups R¹ and R² may also denote H.

Preferably, the groups R¹, R² independently of one another represent H,C₁₋₆-alkyl, C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₃-alkyl,ω-hydroxy-C₂₋₃-alkyl, ω-(C₁₋₄-alkoxy)-C₂₋₃-alkyl,C₁₋₄-alkoxy-carbonyl-C₁₋₄-alkyl, carboxyl-C₁₋₄-alkyl, amino-C₂₋₄-alkyl,C₁₋₄-alkyl-amino-C₂₋₄-alkyl, di-(C₁₋₄-alkyl)-amino-C₂₋₄-alkyl,cyclo-C₃₋₆-alkyleneimino-C₂₋₄-alkyl, pyrrolidin-3-yl,N-(C₁₋₄-alkyl)-pyrrolidinyl, pyrrolidinyl-C₁₋₃-alkyl,N-(C₁₋₄-alkyl)-pyrrolidinyl-C₁₋₃-alkyl, piperidinyl,N-(C₁₋₄-alkyl)-piperidinyl, piperidinyl-C₁₋₃-alkyl,N-(C₁₋₄-alkyl)-piperidinyl-C₁₋₃-alkyl, phenyl, phenyl-C₁₋₃-alkyl,pyridyl or pyridyl-C₁₋₃-alkyl, while in the above-mentioned groups andresidues one or more C atoms may be mono- or polysubstituted by F and/orone or two C atoms may be monosubstituted independently of one anotherby Cl or Br, and the phenyl or pyridyl group may be mono- orpolysubstituted by the above-defined group R¹² and/or may bemonosubstituted by nitro. Preferred substituents of the above-mentionedphenyl or pyridyl groups are selected from among F, Cl, Br, I, cyano,C₁₋₄-alkyl, C₁₋₄-alkoxy, difluoromethyl, trifluoromethyl, hydroxy,amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, acetylamino,aminocarbonyl, difluoromethoxy, trifluoromethoxy, amino-C₁₋₃-alkyl,C₁₋₃-alkylamino-C₁₋₃-alkyl- and di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl, whilea phenyl group may also be monosubstituted by nitro.

Particularly preferably, at least one of the groups R¹, R², and mostparticularly preferably both groups, have a meaning other than H.

If R¹ and R² form an alkylene bridge, it is preferably a C₃₋₇-alkylenebridge, wherein

-   -   a —CH₂— group not adjacent to the N atom of the R¹R²N group may        be replaced by —CH═N— or —CH═CH— and/or    -   a —CH₂— group which is preferably not adjacent to the N atom of        the R¹R²N group may be replaced by —O—, —S—, —C(═N—R¹⁸)—, —C—O,        —C(═CH₂)— or —NR¹³— in such a way that heteroatoms are not        directly joined together,

while in the alkylene bridge defined hereinbefore one or more H atomsmay be replaced by R¹⁴, and

the alkylene bridge defined hereinbefore may be substituted by a carbo-or heterocyclic group Cy in such a way that the bond between thealkylene bridge and the group Cy is made

-   -   via a single bond,    -   via a common C atom forming a spirocyclic ring system,    -   via two common adjacent C and/or N atoms forming a fused        bicyclic ring system or    -   via three or more C and/or N atoms forming a bridged ring        system.

Also preferably, R¹ and R² form an alkylene bridge in such a way thatR¹R²N— denotes a group selected from azetidine, pyrrolidine, piperidine,azepan, 2,5-dihydro-1H-pyrrole, 1,2,3,6-tetrahydro-pyridine,2,3,4,7-tetrahydro-1H-azepine, 2,3,6,7-tetrahydro-1H-azepine,piperazine, wherein the free imine function is substituted by R¹³,piperidin-4-one, piperidin-4-one-oxime,piperidin-4-one-O—C₁₋₄-alkyl-oxime, morpholine and thiomorpholine, whileaccording to the general definition of R¹ and R² one or more H atoms maybe replaced by R¹⁴, and/or the above-mentioned groups may be substitutedby one or two identical or different carbo- or heterocyclic groups Cy ina manner specified according to the general definition of R¹ and R².Particularly preferred groups Cy are C₃₋₇-cycloalkyl,aza-C₄₋₇-cycloalkyl, particularly cyclo-C₃₋₆-alkyleneimino, as well as1-C₁₋₄-alkyl-aza-C₄₋₇-cycloalkyl.

The C₂₋₈-alkylene bridge formed by R¹ and R², wherein —CH₂— groups maybe replaced as specified, may be substituted by one or two identical ordifferent carbo- or heterocyclic groups Cy, as described.

In the event that the alkylene bridge is linked to a group Cy via asingle bond, Cy is preferably selected from among C₃₋₇-cycloalkyl,cyclo-C₃₋₆-alkyleneimino, 1H-imidazole, thienyl and phenyl.

In the event that the alkylene bridge is linked to a group Cy via acommon C atom forming a spirocyclic ring system, Cy is preferablyselected from among C₃₋₇-cycloalkyl, aza-C₄₋₈-cycloalkyl,oxa-C₄₋₈-cycloalkyl, 2,3-dihydro-1H-quinazolin-4-one.

In the event that the alkylene bridge is linked to a group Cy via twocommon adjacent C and/or N atoms forming a fused bicyclic ring system,Cy is preferably selected from among C₄₋₇-cycloalkyl, phenyl, thienyl.

In the event that the alkylene bridge is linked to a group Cy via threeor more C and/or N atoms forming a bridged ring system, Cy preferablydenotes C₄₋₈-cycloalkyl or aza-C₄₋₈-cycloalkyl.

Particularly preferably, the group

is defined according to one of the following partial formulae

wherein one or more H atoms of the heterocycle formed by the groupR¹R²N— may be replaced by R¹⁴ and the ring attached to the heterocycleformed by the group R¹R²N— may be mono- or polysubstituted by R²⁰ at oneor more C atoms, in the case of a phenyl ring may also additionally bemonosubstituted by nitro and

-   X′, X″ independently of one another denote a single bond or    C₁₋₃-alkylene and    -   in the event that the group Y is linked to X′ or X″ via a C        atom, also denotes —C₁₋₃-alkylene-O—, —C₁₋₃-alkylene-NH— or        —C₁₋₃-alkylene-N(C₁₋₃-alkyl)-, and-   X″ additionally also denotes —O—C₁₋₃-alkylene-, —NH—C₁₋₃-alkylene-    or —N(C₁₋₃-alkyl)-C₁₋₃-alkylene- and    -   in the event that the group Y is linked to X″ via a C atom, also        denotes —NH—, —N(C₁₋₃-alkyl)- or —O—,    -   while in the meanings given for X′, X″ hereinbefore, in each        case a C atom may be substituted by R¹⁰, preferably by a        hydroxy, ω-hydroxy-C₁₋₃-alkyl, ω-(C₁₋₄-alkoxy)-C₁₋₃-alkyl and/or        C₁₋₄-alkoxy group, and/or one or two C atoms in each case may be        substituted by one or two identical or different substituents        selected from C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,        C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₃-alkyl, C₄₋₇-cycloalkenyl        and C₄₋₇-cycloalkenyl-C₁₋₃-alkyl, while two alkyl and/or alkenyl        substituents may be joined together, forming a carbocyclic ring        system, and    -   in X′, X″ independently of one another in each case one or more        C atoms may be mono- or polysubstituted by F and/or in each case        one or two C atoms independently of one another may be        monosubstituted by Cl or Br and

wherein R², R¹⁰, R¹³, R¹⁴, R²⁰, R²¹ and X have the meanings given aboveand hereinafter.

In the preferred and particularly preferred meanings of R¹R²N listedabove the following definitions of the substituent R¹⁴ are preferred:C₁₋₄-alkyl, C₂₋₄-alkenyl, C₂₋₄-alkynyl, C₃₋₇-cycloalkyl,C₃₋₇-cycloalkyl-C₁₋₃-alkyl, hydroxy, ω-hydroxy-C₁₋₃-alkyl, C₁₋₄-alkoxy,ω-(C₁₋₄-alkoxy)-C₁₋₃-alkyl, C₁₋₄-alkyl-carbonyl, carboxy,C₁₋₄-alkoxy-carbonyl, hydroxy-carbonyl-C₁₋₃-alkyl,C₁₋₄-alkoxycarbonyl-C₁₋₃-alkyl, C₁₋₄-alkoxy-carbonylamino,C₁₋₄-alkoxy-carbonylamino-C₁₋₃-alkyl, amino, C₁₋₄-alkyl-amino,C₃₋₇-cycloalkyl-amino, N-(C₃₋₇-cycloalkyl)-N-(C₁₋₄-alkyl)-amino,di-(C₁₋₄-alkyl)-amino, amino-C₁₋₃-alkyl, C₁₋₄-alkyl-amino-C₁₋₃-alkyl,C₃₋₇-cycloalkyl-amino-C₁₋₃-alkyl,N-(C₃₋₇-cycloalkyl)-N-(C₁₋₄-alkyl)-amino-C₁₋₃-alkyl,di-(C₁₋₄-alkyl)-amino-C₁₋₃-alkyl, cyclo-C₃₋₆-alkyleneimino-C₁₋₃-alkyl,aminocarbonyl, C₁₋₄-alkyl-amino-carbonyl,C₃₋₇-cycloalkyl-amino-carbonyl,N-(C₃₋₇-cycloalkyl)-N-(C₁₋₄-alkyl)-amino-carbonyl,di-(C₁₋₄-alkyl)-amino-carbonyl, pyridinyl-oxy, pyridinyl-amino,pyridinyl-C₁₋₃-alkyl-amino.

Most particularly preferred meanings of the substituent R¹⁴ areC₁₋₄-alkyl, hydroxy, ω-hydroxy-C₁₋₃-alkyl, C₁₋₄-alkoxy andω-(C₁₋₄-alkoxy)-C₁₋₃-alkyl.

Preferably X denotes a single bond or a C₁₋₄-alkylene bridge, wherein

-   -   a —CH₂— group may be replaced by —CH═CH— or —C≡C— and/or    -   a —CH₂— group may be replaced by —O—, —S—, —CO— or —NR⁴— in such        a way that in each case two O, S or N atoms or an O and an S        atom are not directly joined together,

while the bridge X may be attached to R¹ including the N atom attachedto R¹ and X, forming a heterocyclic group, while the bridge X mayadditionally also be linked to R² including the N atom attached to R²and X, forming a heterocyclic group, and

while two C atoms or a C and an N atom of the alkylene bridge may bejoined together by an additional C₁₋₄-alkylene bridge, and

a C atom may be substituted by R¹⁰ and/or one or two C atoms in eachcase may be substituted by one or two identical or differentsubstituents selected from C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₃-alkyl, C₄₋₇-cycloalkenyl andC₄₋₇-cycloalkenyl-C₁₋₃-alkyl, while two alkyl and/or alkenylsubstituents may be joined together, forming a carbocyclic ring system,particularly a cyclopropyl, cyclobutyl or cyclopentyl group.

If in the group X a —CH₂— group of the alkylene bridge is replacedaccording to the invention, this —CH₂— group is preferably not attacheddirectly to a heteroatom, a double or triple bond.

Preferably the alkylene bridge X, X′ or X″ has no or at most one iminogroup. The position of the imino group within the alkylene bridge X, X′or X″ is preferably selected so that no animal function is formedtogether with the amino group NR¹R² or another adjacent amino group ortwo N atoms are not adjacent to each other.

Preferably X denotes a single bond or C₁₋₄-alkylene and

in the event that the group Y is linked to X via a C atom, it alsodenotes —CH₂—CH═CH—, —CH₂—C≡C—, C₂₋₄-alkylenoxy, C₂₋₄-alkylene-NR⁴,C₂₋₄-alkylene-NR⁴—C₂₋₄-alkylene-O, 1,2- or 1,3-pyrrolidinylene or 1,2-,1,3- or 1,4-piperidinylene, while the pyrrolidinylene and piperidinylenegroups are bound to Y via the imino group,

while the bridge X may be attached to R¹ including the N atom attachedto R¹ and X, forming a heterocyclic group, and the bridge X mayadditionally also be attached to R², including the N atom attached to R²and X, forming a heterocyclic group, and

in X a C atom may be substituted by R¹⁰, preferably a hydroxy,ω-hydroxy-C₁₋₃-alkyl, ω-(C₁₋₄-alkoxy)-C₁₋₃-alkyl- and/or C₁₋₄-alkoxygroup, and/or one or two C atoms in each case may be substituted by oneor two identical or different substituents selected from C₁₋₆-alkyl,C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₃-alkyl,C₄₋₇-cycloalkenyl and C₄₋₇-cycloalkenyl-C₁₋₃-alkyl, while two alkyland/or alkenyl substituents may be joined together, forming acarbocyclic ring system, and

in the above-mentioned groups and residues one or more C atoms may bemono- or polysubstituted by F and/or one or two C atoms independently ofone another may be monosubstituted by Cl or Br and

R¹, R⁴ and R¹⁰ are as hereinbefore defined.

Particularly preferably X denotes —CH₂—, —CH₂—CH₂— or —CH₂—CH₂—CH₂— andin the event that the group Y is bonded to X via a C atom, it alsodenotes —CH₂—C≡C— —CH₂—CH₂—O—, —CH₂—CH₂—NR⁴— or 1,3-pyrrolidinylene,while the pyrrolidinylene group is linked to Y via the imino group, and

the bridge X may be attached to R¹ including the N atom attached to R¹and X, forming a heterocyclic group, and the bridge X may additionallyalso be attached to R², including the N atom attached to R² and X,forming a heterocyclic group, and

in X a C atom may be substituted by R¹⁰, preferably a hydroxy,ω-hydroxy-C₁₋₃-alkyl, ω-(C₁₋₄-alkoxy)-C₁₋₃-alkyl and/or C₁₋₄-alkoxygroup, and/or one or two C atoms in each case may be substituted by oneor two identical or different substituents selected from C₁₋₆-alkyl,C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₃-alkyl,C₄₋₇-cycloalkenyl and C₄₋₇-cycloalkenyl-C₁₋₃-alkyl, while two alkyland/or alkenyl substituents may be joined together, forming acarbocyclic ring system, and

in each case one or more C atoms may be mono- or polysubstituted by Fand/or in each case one or two C atoms independently of one another maybe monosubstituted by Cl or Br.

If in the group X, X′ or X″ one or more C atoms is or are substituted bya hydroxy and/or C₁₋₄-alkoxy group, the substituted C atom is preferablynot directly adjacent to another heteroatom.

If in X, X′ or X″ a C atom is substituted, preferred substituents areselected from among C₁₋₄-alkyl, C₂₋₄-alkenyl, C₂₋₄-alkynyl,C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₃-alkyl, hydroxy,ω-hydroxy-C₁₋₃-alkyl, ω-(C₁₋₄-alkoxy)-C₁₋₃-alkyl- and C₁₋₄-alkoxygroups. Moreover in X, X′ or X″ a C atom may be disubstituted and/or oneor two C atoms may be mono- or disubstituted, while preferredsubstituents are selected from among C₁₋₄-alkyl, C₂₋₄-alkenyl,C₂₋₄-alkynyl, C₃₋₇-cycloalkyl and C₃₋₇-cycloalkyl-C₁₋₃-alkyl, and twoC₁₋₄-alkyl and/or C₂₋₄-alkenyl substituents may also be joined together,forming a saturated or monounsaturated carbocyclic ring.

Most particularly preferred substituents of one or two C atoms in X, X′or X″ are selected from methyl, ethyl, n-propyl, i-propyl, cyclopropyl,cyclopropylmethyl, while two alkyl substituents may also be joinedtogether at a C atom, forming a carbocyclic ring.

If X denotes an alkylene bridge, the —CH₂— group adjacent to the R¹R²N—group is preferably not replaced by —O—, —S—, —(SO)—, —(SO₂)—, —CO— or—NR⁴—.

Most particularly preferably, X denotes —CH₂—, —CH₂—CH₂— or—CH₂—CH₂—CH₂— and in the event that the group Y is attached to X via a Catom, also denotes —CH₂—CH₂—O—, —CH(CH₃)—CH₂—O—, —CH₂—CH(CH₃)—O—,—CH₂—CH₂—NH—, —CH(CH₃)—CH₂—NH— or —CH₂—CH₂—N(CH₃)—. In the event that R¹and/or R² have an amine function, which may also be substituted, anotherparticularly preferred meaning of X is a single bond.

According to a first preferred embodiment according to the invention Zdenotes a single bond.

In a second preferred embodiment according to the invention Z is aC₁₋₄-alkylene bridge, which may be substituted and/or wherein a —CH₂—group may be replaced as specified.

Preferred definitions of the groups W and/or Z, particularly the groupZ, are, independently of one another, a single bond or a bridge selectedfrom among —CH₂—, —CH₂—CH₂—, —CH₂—CH(CH₃)—, —CH₂—C(CH₃)₂—,—CH(CH₃)—CH₂—, —C(CH₃)₂—CH₂—, cyclopropylene, —CH₂—CH(R¹⁰)— and—CH(R¹⁰)—CH₂—. Additional particularly preferred definitions of thegroup W are also —CH₂—O— or —CH₂—NR⁴—. Additional particularly preferreddefinitions of the group Z are also —O—CH₂— or —NR⁴—CH₂—.

According to one preferred embodiment according to the invention Wdenotes a single bond.

Preferably W and/or Z independently of one another represent a singlebond, —CH₂—, —CH₂—CH₂—, —CH₂—CH₂—CH₂—, 1,1-cyclopropylene or1,2-cyclopropylene.

W may preferably additionally also represent —CH₂—O—, —CH₂—CH₂—O—,—CH₂—NR⁴— or —CH₂—CH₂—NR⁴—.

In addition to the definitions given above Z may also preferablyrepresent —O—CH₂—, —O—CH₂—CH₂—, —NR⁴—CH₂— or —NR⁴—CH₂—CH₂—.

In the above-mentioned definitions of the groups W and Z a C atom may besubstituted by R¹⁰, preferably by a hydroxy, ω-hydroxy-C₁₋₃-alkyl,ω-(C₁₋₄-alkoxy)-C₁₋₃-alkyl and/or C₁₋₄-alkoxy group, and/or one or two Catoms may each independently of one another be substituted by one or twoidentical or different C₁₋₄-alkyl groups, while two alkyl groups may bejoined together, forming a carbocyclic group, particularly acyclopropyl, cyclobutyl or cyclopentyl group. Moreover in each case oneor more C atoms in the groups W and Z may be mono- or polysubstituted byF and/or in each case one or two C atoms may each independently of oneanother be monosubstituted by Cl or Br.

In the event that the bridge X comprises a carbonyl group, W and Zpreferably do not contain an —O— bridge.

In the definitions of the groups W and/or Z, R⁴ has the meanings givenabove, preferably —H, methyl, ethyl, propyl or iso-propyl.

In the definitions of the groups W and/or Z, R¹⁰ has the meanings givenabove, preferably —OH, N-pyrrolidinyl, amino-ethoxy,C₁₋₄-alkyl-amino-ethoxy or di-(C₁₋₄-alkyl)-amino-ethoxy.

In the above-mentioned definitions of the groups W and/or Z in each caseone or more C atoms may be mono- or polysubstituted by F and/or in eachcase one or two C atoms independently of one another may bemonosubstituted by Cl or Br.

If in the group W and/or Z one or two C atoms are substituted by ahydroxy and/or C₁₋₃-alkoxy group, the substituted C atom is preferablynot immediately adjacent to another heteroatom.

According to one embodiment compounds of formula I according to theinvention have W and Z bridges, while precisely one or both of thebridges W and Z represent a single bond.

A preferred definition of the group Y is aryl or heteroaryl.

The group Y preferably has a meaning which is selected from the group ofthe bivalent cyclic groups phenyl, naphthyl, thienyl, benzothienyl,tetrahydronaphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,indolyl, dihydroindolyl, dihydroindolonyl, quinolinyl,tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indazolyl,benzimidazolyl, benzofuranyl or benzoxazolyl, while the above-mentionedcyclic groups may be mono- or polysubstituted at one or more C atoms byR²⁰, or in the case of a phenyl group may also additionally bemonosubstituted by nitro, and/or substituted by R²¹ at one or more Natoms. R¹ may be attached to Y and/or X may be attached to Y ashereinbefore defined.

Particularly preferably, a definition of the group Y is selected fromamong the bivalent cyclic groups

The cyclic groups listed above may be mono- or polysubstituted by R²⁰ atone or more C atoms, and in the case of a phenyl group may alsoadditionally be monosubstituted by nitro, and/or one or more NH groupsmay be substituted by R²¹.

Most particularly preferably, Y is one of the groups listed below

particularly a 1,4-phenylene group, while the groups listed may besubstituted as specified.

Particularly preferred substituents R²⁰ of the group Y are selected fromamong fluorine, chlorine, bromine, C₁₋₄-alkyl, C₂₋₆-alkenyl, —CHO,hydroxy, ω-hydroxy-C₁₋₃-alkyl, C₁₋₄-alkoxy, trifluoromethyl,trifluoromethoxy, C₂₋₄-alkynyl, carboxy, C₁₋₄-alkoxycarbonyl,ω-(C₁₋₄-alkoxy)-C₁₋₃-alkyl, C₁₋₄-alkoxy-carbonylamino, amino,C₁₋₄-alkyl-amino, di-(C₁₋₄-alkyl)-amino, aminocarbonyl,C₁₋₄-alkyl-amino-carbonyl, di-(C₁₋₄-alkyl)-amino-carbonyl, —CH═N—OH and—CH═N—O—C₁₋₄-alkyl.

A preferred definition of the group A is aryl or heteroaryl.

Preferably the group A is selected from among the bivalent cyclic groupsphenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, which may bemay be mono- or polysubstituted at one or more C atoms by R²⁰, and inthe case of a phenyl ring may also additionally be monosubstituted bynitro.

Most particularly preferably, A is one of the groups listed below

while the groups listed may be substituted as specified hereinbefore.

Particularly preferred substituents R²⁰ of the group A are fluorine,chlorine, bromine, methoxy and C₁₋₃-alkyl.

Preferably the groups A and/or Y are unsubstituted or monosubstituted byR²⁰ as specified. The group A is preferably unsubstituted ormonofluorinated.

According to a first embodiment, the definition of the group B ispreferably selected from among the unsaturated carbo- and heterocyclesphenyl, thienyl and furanyl. Particularly preferably, the group Bdenotes phenyl. The group B in the definitions provided may be mono- orpolysubstituted by R²⁰, a phenyl group may additionally also bemonosubstituted by nitro. Preferably the group B is mono-, di- ortrisubstituted, particularly mono- or disubstituted. In the case of amonosubstitution the substituent is preferably in the para position tothe group A.

Particularly preferred substituents R²⁰ of the group B are selected fromamong fluorine, chlorine, bromine, cyano, nitro, C₁₋₄-alkyl, hydroxy,ω-hydroxy-C₁₋₃-alkyl, C₁₋₄-alkoxy, difluoromethyl, trifluoromethyl,difluoromethoxy, trifluoromethoxy, C₂₋₄-alkynyl, carboxy,C₁₋₄-alkoxycarbonyl, ω-(C₁₋₄-alkoxy)-C₁₋₃-alkyl,C₁₋₄-alkoxy-carbonylamino, amino, C₁₋₄-alkyl-amino,di-(C₁₋₄-alkyl)-amino, aminocarbonyl, C₁₋₄-alkyl-amino-carbonyl anddi-(C₁₋₄-alkyl)-amino-carbonyl.

Most particularly preferred substituents R²⁰ of the group B are selectedfrom among fluorine, chlorine, bromine, CF₃, C₁₋₃-alkyl and C₁₋₄-alkoxy.

According to a second embodiment the definition of the group B ispreferably selected from C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,C₃₋₇-cycloalkyl-C₁₋₃-alkyl, C₃₋₇-cycloalkenyl-C₁₋₃-alkyl,C₃₋₇-cycloalkyl-C₁₋₃-alkenyl, C₃₋₇-cycloalkyl-C₁₋₃-alkynyl, while one ormore C atoms in the groups mentioned for B hereinbefore may be mono- orpolysubstituted by fluorine.

In the cyclic groups according to the embodiment mentioned hereinbeforeone or more C atoms may be substituted by R²⁰.

Particularly preferred according to this embodiment are the groupsC₃₋₆-alkyl, C₃₋₆-alkenyl, C₃₋₆-alkynyl, cyclopentyl, cyclopentenyl,cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl,cyclopentyl-C₁₋₃-alkyl, cyclopentenyl-C₁₋₃-alkyl, cyclohexyl-C₁₋₃-alkyl,cyclohexenyl-C₁₋₃-alkyl, cycloheptyl-C₁₋₃-alkyl,cycloheptenyl-C₁₋₃-alkyl, while one or more C atoms in the groupsmentioned for B hereinbefore may be mono- or polysubstituted byfluorine.

R⁴ and/or R⁵ have one of the meanings given for R¹⁷, preferably for R¹⁶.Particularly preferred meanings of R⁴ and/or R⁵ are H, C₁₋₄-alkyl,C₃₋₇-cycloalkyl and C₃₋₇-cycloalkyl-C₁₋₃-alkyl.

If R¹¹ is a C₂₋₆-alkenyl or C₂₋₆-alkynyl group, the meanings —CH═CH₂,—CH═CH(CH₃), —CH═C(CH₃)₂ and —C≡CH, —C≡C—CH₃ are preferred.

Preferred definitions of the group R²⁰ are halogen, hydroxy, cyano,C₁₋₄-alkyl, C₁₋₄-alkoxy, C₃₋₇-cycloalkyl and C₁₋₄-alkoxy-C₁₋₃-alkyl,while C atoms may be mono- or polysubstituted by fluorine andmonosubstituted by Cl or Br. Particularly preferably, R²⁰ denotes F, Cl,Br, I, OH, cyano, methyl, difluoromethyl, trifluoromethyl, ethyl,n-propyl, iso-propyl, methoxy, difluoromethoxy, trifluoromethoxy,ethoxy, n-propoxy or iso-propoxy.

Preferred definitions of the group R²¹ are C₁₋₄-alkyl,C₁₋₄-alkylcarbonyl, C₁₋₄-alkylsulphonyl, —SO₂—NH₂, —SO₂—NH—C₁₋₃-alkyl,—SO₂—N(C₁₋₃-alkyl)₂ and cyclo-C₃₋₆-alkyleneimino-sulphonyl.

Cy preferably denotes a C₃₋₇-cycloalkyl, particularly a C₅₋₇-cycloalkylgroup, a C₅₋₇-cycloalkenyl group, aryl or heteroaryl, while aryl orheteroaryl preferably denotes a monocyclic or fused bicyclic ringsystem, and the above-mentioned cyclic groups may be mono- orpolysubstituted by R²⁰ at one or more C atoms, and in the case of aphenyl group may also additionally be monosubstituted by nitro, and/orone or more NH groups may be substituted by R²¹.

Preferred compounds according to the invention are those wherein one ormore of the groups, residues, substituents and/or indices have one ofthe meanings mentioned above as being preferred.

Particularly preferred compounds according to the invention are thosewherein

-   Y has one of the meanings mentioned above as being preferred, most    preferably a group selected from

-   -    and/or

-   A has one of the meanings mentioned above as being preferred, and    most preferably denotes

-   -    and/or

-   B has one of the meanings mentioned above as being preferred, most    preferably phenyl,

while A, B and/or Y may be mono- or disubstituted, B may also betrisubstituted by, or substituted by R²⁰ at one or more C atoms, and inthe case of a phenyl ring may also additionally be monosubstituted bynitro.

Most particularly preferred compounds according to the invention arethose wherein A, B, X, Y, Z, R¹, R² and W independently of one anotherhave the preferred meanings given above.

Particularly preferred compounds according to the invention aretherefore described by one of general formulae IIa to IIL

wherein

-   R¹, R², X and Z have the above-mentioned meanings and-   Q denotes —CH— or N, preferably —CH—, and-   L¹, L²,-   L³, L⁴ denote H or have one of the meanings given for R²⁰, and-   L⁵ denote H or has one of the meanings given for R²¹, and-   m, n,-   p, q independently of one another represent the values 0, 1 or 2,    and p may also have the value 3.

One group of most particularly preferred compounds can be described bythe formula IIa wherein the group Q denotes —CH—.

Preferably, particularly in formulae IIa to IIL, the above-mentionedgroups have the following meanings:

-   X denotes —CH₂—, —CH₂—CH₂— or —CH₂—CH₂—CH₂—,    -   in formulae IIa to IIe it also denotes —CH₂—C≡C—, —CH₂—CH₂—O—,        —CH₂—CH₂—NR⁴— or 1,3-pyrrolidinylene, while the pyrrolidinylene        group is linked to Y via the imino group,    -   while in the definitions given hereinbefore one or two —CH₂—        groups may be substituted by one or two methyl groups,    -   while the bridge X may be connected to R¹ including the N atom        attached to R¹ and X, forming a heterocyclic group, and-   Z denotes a single bond or a bridge selected from among —CH₂—,    —CH₂—CH₂—, —CH₂—CH(CH₃)—, —CH₂—C(CH₃)₂—, —CH(CH₃)—CH₂—,    —C(CH₃)₂—CH₂—, cyclopropylene, —CH₂—CH(R¹⁰)— and —CH(R¹⁰)—CH₂—,    —O—CH₂— or —NR⁴—CH₂—.

In the definitions of X and Z provided hereinbefore, in each case a Catom may be substituted by a hydroxy, ω-hydroxy-C₁₋₃-alkyl,ω-(C₁₋₄-alkoxy)-C₁₋₃-alkyl and/or C₁₋₄-alkoxy group, and/or one or two Catoms independently of one another may each be substituted by one or twoidentical or different C₁₋₄-alkyl groups, while the alkyl groups may bejoined together, forming a carbocyclic ring. In addition, in the groupsX and Z in each case one or more C atoms may be mono- or polysubstitutedby F and/or in each case one or two C atoms independently of one anothermay be monosubstituted by Cl or Br.

In the definitions of X and Z R⁴ has the meanings given hereinbefore,preferably —H, methyl, ethyl, propyl or iso-propyl.

In the definitions of X and Z R¹⁰ has the meanings given hereinbefore,preferably —OH, N-pyrrolidinyl, amino-ethoxy, C₁₋₄-alkyl-amino-ethoxy ordi-(C₁₋₄-alkyl)-amino-ethoxy.

Most particularly preferably,

-   X denotes —CH₂—, —CH₂—CH₂— or —CH₂—CH₂—CH₂—,    -   and in formulae IIa to IIe it also denotes —CH₂—CH═CH—,        —CH₂—C≡C—, —CH₂—CH₂—O—, —CH(CH₃)—CH₂—O— or —CH₂—CH(CH₃)—O—,        and/or-   Z denotes a single bond, —CH₂—, —CH₂—CH₂— or —O—CH₂—, particularly a    single bond or —CH₂—CH₂— and/or-   L¹, L²,-   L³, L⁴, independently of one another denote F, Cl, Br, I, OH, cyano,    C₁₋₄-alkyl, C₂₋₄-alkynyl, C₁₋₄-alkoxy, difluoromethyl,    trifluoromethyl, amino, C₁₋₄-alkylamino, di-(C₁₋₄-alkyl)-amino,    acetylamino, aminocarbonyl, difluoromethoxy, trifluoromethoxy,    amino-C₁₋₃-alkyl, C₁₋₄-alkylamino-C₁₋₃-alkyl or    di-(C₁₋₄-alkyl)-amino-C₁₋₃-alkyl or nitro, with the proviso that a    phenyl may only be monosubstituted by nitro, and/or-   L¹ additionally also denotes —CH═N—OH or —CH═N—O—C₁₋₄-alkyl,-   m, n, q denote 0 or 1 and/or-   p denotes 1, 2 or 3, particularly 1 or 2.

The following individual compounds are particularly preferred:

-   5-(4-chloro-phenyl)-2-[5-(2-pyrrolidin-1-yl-ethoxy)-pyridin-2-yl-ethynyl]-pyridine

-   [(R)-1-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-ethyl)-pyrrolidin-2-yl]-methanol

-   5-(4-chloro-phenyl)-2-[2-(4-methyl-piperidin-1-ylmethyl)-benzofuran-5-ylethynyl]-pyridine

-   5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-1-(2-pyrrolidin-1-yl-ethyl)-1,3-dihydro-benzimidazol-2-one

-   [1-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-ethyl)-piperidin-4-yl]-methanol

-   1-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxy}-ethyl)-piperidin-3-ol

-   N-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-2-pyrrolidin-1-yl-propionamide

-   1-{3-[5-(4-chloro-phenyl)-pyridin-2-yl]-prop-2-ynyl}-5-pyrrolidin-1-ylmethyl-1H-indole

-   2-[4-(4-azetidin-1-ylmethyl-phenyl)-but-1-ynyl]-5-(4-chloro-phenyl)-pyridine

-   5-(4-chloro-phenyl)-2-[4-(4-piperidin-1-ylmethyl-phenyl)-but-1-ynyl]-pyridine

-   5-(4-bromo-phenyl)-2-[4-(4-pyrrolidin-1-ylmethyl-phenyl)-but-1-ynyl]-pyridine

-   2-[(4-{4-[5-(4-chloro-phenyl)-pyridin-2-yl]-but-3-ynyl}-benzyl)-methyl-amino]-ethanol

-   5-(4-chloro-phenyl)-2-{4-[4-((S)-2-methoxymethyl-pyrrolidin-1-ylmethyl)-phenyl]-but-1-ynyl}-pyridine

-   5-(4-chloro-phenyl)-2-{4-[2-(4-propyl-piperidin-1-yl)-ethoxy]-phenylethynyl}-pyridine

-   5′-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-3-pyrrolidin-1-yl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl

-   5-(4-chloro-phenyl)-2-{4-[4-(2-methyl-pyrrolidin-1-ylmethyl)-phenyl]-but-1-ynyl}-pyridine

-   3-(4-chloro-phenyl)-6-[4-(4-pyrrolidin-1-ylmethyl-phenyl)-but-1-ynyl]-pyridazine

-   5-(4-chloro-phenyl)-2-[4-(4-pyrrolidin-1-ylmethyl-phenyl)-but-1-ynyl]-pyridine

-   5-(4-chloro-phenyl)-2-{4-[2-(2,6-dimethyl-piperidin-1-yl)-ethoxy]-3-methyl-phenylethynyl}-pyridine

-   methyl    5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-(2-pyrrolidin-1-yl-ethoxy)-benzoate

-   5-(4-chloro-phenyl)-2-[3-methyl-4-(2-piperidin-1-yl-ethoxy)-phenylethynyl]-pyridine

-   5-(4-chloro-phenyl)-2-[3-methyl-4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridine

-   5-(4-chloro-phenyl)-2-{4-[4-(4-methyl-piperidin-1-ylmethyl)-phenyl]-but-1-ynyl}-pyridine

-   1-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxy}-ethyl)-piperidin-4-ol

-   5-(4-chloro-phenyl)-2-{3-methyl-4-[2-(2-pyrrolidin-1-ylmethyl-piperidin-1-yl)-ethoxy]-phenylethynyl}-pyridine

-   {5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-(2-piperidin-1-yl-ethyl)-amine

-   4-(4-{4-[5-(4-chloro-phenyl)-pyridin-2-yl]-but-3-ynyl}-benzyl)-morpholine

-   (4-{4-[5-(4-chloro-phenyl)-pyridin-2-yl]-but-3-ynyl}-benzyl)-methyl-piperidin-4-yl-amine

-   5-(4-chloro-phenyl)-2-[3-(4-pyrrolidin-1-ylmethyl-phenoxy)-prop-1-ynyl]-pyridine

-   6-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-pyrrolidin-1-ylmethyl-1,2,3,4-tetrahydro-quinoline

-   (1-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-pyrrolidin-3-yl)-dimethyl-amine

-   [(S)-1-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxy}-ethyl)-pyrrolidin-2-yl]-methanol

-   5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-(2-pyrrolidin-1-yl-ethoxy)-phenylamine

-   {5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-(2-pyrrolidin-1-yl-propyl)-amine

-   1-(4-{4-[5-(4-chloro-phenyl)-pyridin-2-yl]-but-3-ynyl}-benzyl)-pyrrolidin-3-ylamine

-   2-[3-bromo-4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-5-(4-chloro-phenyl)-pyridine

-   1-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxy}-ethyl)-azepan

-   5-(4-chloro-phenyl)-2-(6-pyrrolidin-1-ylmethyl-naphthalen-2-ylethynyl)-pyridine

-   5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-N-methyl-2-(2-pyrrolidin-1-yl-ethoxy)-benzamide

-   (2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxy}-ethyl)-cyclopropylmethyl-propyl-amine

-   1-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-ethyl)-4-methyl-piperidin-4-ol

-   5-(4-chloro-phenyl)-2-{3-methyl-4-[2-(4-methyl-piperidin-1-yl)-ethoxy]-phenylethynyl}-pyridine

-   5-(4-chloro-phenyl)-3-fluoro-2-{4-[2-(4-methyl-piperidin-1-yl)-ethoxy]-phenylethynyl}-pyridine

-   5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-1-(2-pyrrolidin-1-yl-ethyl)-1H-indole

-   {4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-(2-pyrrolidin-1-yl-ethyl)-amine

-   methyl    [1-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxy}-ethyl)-piperidin-4-yl]-acetate

-   {5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-methyl-(2-pyrrolidin-1-yl-ethyl)-amine

-   tert-butyl    [1-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-ethyl)-pyrrolidin-3-yl]-carbaminate

-   5-(4-chloro-phenyl)-2-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridine

-   5-(4-chloro-phenyl)-2-[4-(2-piperidin-1-yl-ethoxy)-phenylethynyl]-pyridine

-   5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-1-(2-pyrrolidin-1-yl-ethyl)-1H-indazole

-   2-[4-(2-azetidin-1-yl-ethoxy)-phenylethynyl]-5-(4-chloro-phenyl)-pyridine

-   5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-(2-pyrrolidin-1-yl-ethoxy)-benzaldehyde    O-methyl-oxime

-   1′-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-[1,3′]bipyrrrolidinyl

-   (4-{4-[5-(4-chloro-phenyl)-pyridin-2-yl]-but-3-ynyl}-benzyl)-methyl-(1-methyl-piperidin-4-yl)-amine

-   5-(4-chloro-phenyl)-2-[3-chloro-4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridine

-   (S)-1-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxy}-ethyl)-pyrrolidin-3-ol

-   [1-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxy}-ethyl)-piperidin-4-yl]-pyridin-2-yl-amine

-   5-(4-bromo-phenyl)-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridine

-   N-[1-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-ethyl)-piperidin-4-ylmethyl]-N-methyl-acetamide

-   5-(2,4-dichloro-phenyl)-2-[4-(4-pyrrolidin-1-ylmethyl-phenyl)-but-1-ynyl]-pyridine

-   5-(4-chloro-phenyl)-2-{4-[2-(4-ethyl-piperidin-1-yl)-ethoxy]-phenylethynyl}-pyridine

-   [1-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxy}-ethyl)-piperidin-4-yl]-methanol

-   5-(4-chloro-phenyl)-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridine

-   5-(4-chloro-phenyl)-2-{4-[2-(3,6-dihydro-2H-pyridine-1-yl)-ethoxy]-phenylethynyl}-pyridine

-   5-(4-chloro-phenyl)-2-{4-[2-(2-methyl-pyrrolidin-1-yl)-ethoxy]-phenylethynyl}-pyridine

-   (4-{4-[5-(4-chloro-phenyl)-pyridin-2-yl]-but-3-ynyl}-benzyl)-cyclopropylmethyl-amine

-   5-(4-chloro-phenyl)-2-{4-[4-(4-pyrrolidin-1-yl-piperidin-1-ylmethyl)-phenyl]-but-1-ynyl}-pyridine

-   5-(4-methoxy-phenyl)-2-[4-(4-pyrrolidin-1-ylmethyl-phenyl)-but-1-ynyl]-pyridine

-   5-(3,4-difluoro-phenyl)-2-[4-(4-pyrrolidin-1-ylmethyl-phenyl)-but-1-ynyl]-pyridine

-   1-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxy}-ethyl)-4-methyl-piperidin-4-ol

-   5-(4-chloro-phenyl)-2-{4-[4-((R)-2-methoxymethyl-pyrrolidin-1-ylmethyl)-phenyl]-but-1-ynyl}-pyridine

-   6-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-pyrrolidin-1-ylmethyl-quinoline

-   1-(4-{4-[5-(4-chloro-phenyl)-pyridin-2-yl]-but-3-ynyl}-benzyl)-4-methyl-piperazine

-   {5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-(2-pyrrolidin-1-yl-ethyl)-amine

-   5-(4-chloro-phenyl)-2-(3-methyl-4-{2-[4-(pyridin-2-yloxy)-piperidin-1-yl]-ethoxy}-phenylethynyl)-pyridine

-   5-(4-chloro-phenyl)-2-{4-[2-(3,6-dihydro-2H-pyridine-1-yl)-ethoxy]-3-methyl-phenylethynyl}-pyridine

-   (R)-1-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxy}-ethyl)-pyrrolidin-3-ol

-   1-(2-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-indol-1-yl}-ethyl)-piperidin-4-ol

-   1-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-ethyl)-piperidin-4-ol

-   1-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxy}-ethyl)-4-phenyl-piperidin-4-ol

-   1-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-ethyl)-[4,4′]bipiperidinyl

-   5-(4-chloro-phenyl)-2-[3-ethynyl-4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridine

-   5-(3,4-dichloro-phenyl)-2-[4-(4-pyrrolidin-1-ylmethyl-phenyl)-but-1-ynyl]-pyridine

-   1-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxy}-ethyl)-4-methyl-piperidin-4-ylamine

-   5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-(2-pyrrolidin-1-yl-ethoxy)-benzaldehyde-oxime

-   5-(4-chloro-phenyl)-2-{4-[2-(2,6-dimethyl-piperidin-1-yl)-ethoxy]-phenylethynyl}-pyridine

-   5-(4-chloro-phenyl)-2-(4-{2-[4-(1H-imidazol-4-yl)-piperidin-1-yl]ethoxy}-3-methyl-phenylethynyl)-pyridine

-   [1-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxy}-ethyl)-piperidin-2-yl]-methanol

-   (4-{4-[5-(4-chloro-phenyl)-pyridin-2-yl]-but-3-ynyl}-benzyl)-methyl-pyridin-2-ylmethyl-amine

-   1-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-ethyl)-piperidin-4-carboxylic    acid amide

-   2-[(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-ethyl)-methyl-amino]-ethanol

-   5-(4-chloro-phenyl)-2-{4-[2-(4-methyl-piperidin-1-yl)-ethoxy]-phenylethynyl}-pyridine

-   {2-[1-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxy}-ethyl)-piperidin-4-yl]-ethyl}-diethyl-amine

-   5-(4-chloro-phenyl)-2-{4-[2-(2,4,6-trimethyl-piperidin-1-yl)-ethoxy]-phenylethynyl}-pyridine

-   5-(4-chloro-phenyl)-2-{4-[2-(3,5-dimethyl-piperidin-1-yl)-ethoxy]-3-methyl-phenylethynyl}-pyridine

-   cis-2-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-ethyl)-decahydro-isoquinoline

-   6-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxy}-ethyl)-2-methyl-2,6-diaza-spiro[3.4]octane

-   1-(2-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-indol-1-yl}-ethyl)-4-methyl-piperidin-4-ol

-   [1-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxy}-ethyl)-pyrrolidin-3-yl]-dimethyl-amine

-   5-(4-chloro-phenyl)-2-[3-fluoro-4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridine

-   [1-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxy}-ethyl)-piperidin-4-yl]-cyclopentyl-methyl-amine

-   5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-1-(2-pyrrolidin-1-yl-ethyl)-2,3-dihydro-1H-indole

-   5-(4-chloro-phenyl)-2-{4-[2-(4-pyrrolidin-1-yl-piperidin-1-yl)-ethoxy]-phenylethynyl}-pyridine

-   5-(4-chloro-phenyl)-2-{4-[2-(2,5-dihydro-pyrrol-1-yl)-ethoxy]-phenylethynyl}-pyridine

-   [1-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-ethyl)-piperidin-4-ylmethyl]-dimethyl-amine

-   1-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-ethyl)-4-methyl-piperazine

-   (4-{4-[5-(4-chloro-phenyl)-pyridin-2-yl]-but-3-ynyl}-benzyl)-pyridin-2-ylmethyl-amine

-   1-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxy}-ethyl)-spiro[piperidin-4,2′(1H′)-quinazolin]-4′(3′H)one

-   4-{[(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxy}-ethyl)-methyl-amino]-methyl}-phenol

-   5-(4-chloro-phenyl)-2-[4-(3-piperidin-1-yl-pyrrolidin-1-yl)-phenylethynyl]-pyridine

-   5-(4-chloro-phenyl)-2-[2-(2-pyrrolidin-1-yl-ethoxy)-pyridin-5-yl-ethynyl]-pyridine

-   3-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxy}-ethyl)-9-methyl-3,9-diaza-spiro[5.5]undecane

-   (2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxy}-ethyl)-diisopropyl-amine

-   5-(4-chloro-phenyl)-2-[4-(3-pyrrolidin-1-yl-propyl)-phenylethynyl]-pyridine

-   2-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-ethyl)-1,2,3,4-tetrahydro-isoquinoline

-   3-(4-chloro-phenyl)-6-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridazine

-   (R)-1-(2-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-indol-1-yl}-ethyl)-pyrrolidin-3-ol

-   5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-3-methyl-1-(2-pyrrolidin-1-yl-ethyl)-1,3-dihydro-benzimidazol-2-one

-   5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-1-(2-pyrrolidin-1-yl-ethyl)-1H-benzimidazole

-   2-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-1-methyl-5-pyrrolidin-1-ylmethyl-1H-benzimidazole

-   trans-2-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-ethyl)-decahydro-isoquinoline

including the tautomers, the diastereomers, the enantiomers, themixtures thereof and the salts thereof.

Some expressions used hereinbefore and below to describe the compoundsaccording to the invention will now be defined more fully.

The term halogen denotes an atom selected from among F, Cl, Br and I,particularly F, Cl and Br.

The term C_(1-n)-alkyl, where n has a value of 3 to 8, denotes asaturated, branched or unbranched hydrocarbon group with 1 to n C atoms.Examples of such groups include methyl, ethyl, n-propyl, iso-propyl,butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl,neo-pentyl, tert-pentyl, n-hexyl, iso-hexyl, etc.

The term C_(1-n)-alkylene, where n may have a value of 1 to 8, denotes asaturated, branched or unbranched hydrocarbon bridge with 1 to n Catoms. Examples of such groups include methylene (—CH₂—), ethylene(—CH₂—CH₂—), 1-methyl-ethylene (—CH(CH₃)—CH₂—), 1,1-dimethyl-ethylene(—C(CH₃)₂—CH₂—), n-prop-1,3-ylene (—CH₂—CH₂—CH₂—),1-methylprop-1,3-ylene (—CH(CH₃)—CH₂—CH₂—), 2-methyl prop-1,3-ylene(—CH₂—CH(CH₃)—CH₂—), etc., as well as the correspondingmirror-symmetrical forms.

The term C_(2-n)-alkenyl, where n has a value of 3 to 6, denotes abranched or unbranched hydrocarbon group with 2 to n C atoms and atleast one C═C-double bond. Examples of such groups include vinyl,1-propenyl, 2-propenyl, iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl,2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl,5-hexenyl etc.

The term C_(2-n)-alkynyl, where n has a value of 3 to 6, denotes abranched or unbranched hydrocarbon group with 2 to n C atoms and a C≡Ctriple bond. Examples of such groups include ethynyl, 1-propynyl,2-propynyl, iso-propynyl, 1-butynyl, 2-butynyl, 3-butynyl,2-methyl-1-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl,3-methyl-2-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl,5-hexynyl etc.

The term C_(1-n)-alkoxy denotes a C_(1-n)-alkyl-O— group, whereinC_(1-n)-alkyl is defined as above. Examples of such groups includemethoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy,sec-butoxy, tert-butoxy, n-pentoxy, iso-pentoxy, neo-pentoxy,tert-pentoxy, n-hexoxy, iso-hexoxy etc.

The term C_(1-n)-alkylthio denotes a C_(1-n)-alkyl-S— group, whereinC_(1-n)-alkyl is defined as above. Examples of such groups includemethylthio, ethylthio, n-propylthio, iso-propylthio, n-butylthio,iso-butylthio, sec-butylthio, tert-butylthio, n-pentylthio,iso-pentylthio, neo-pentylthio, tert-pentylthio, n-hexylthio,iso-hexylthio, etc.

The term C_(1-n)-alkylcarbonyl denotes a C_(1-n)-alkyl-C(═O)— group,wherein C_(1-n)-alkyl is defined as above. Examples of such groupsinclude methylcarbonyl, ethylcarbonyl, n-propylcarbonyl,iso-propylcarbonyl, n-butylcarbonyl, iso-butylcarbonyl,sec-butylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl,iso-pentylcarbonyl, neo-pentylcarbonyl, tert-pentylcarbonyl,n-hexylcarbonyl, iso-hexylcarbonyl, etc.

The term C_(3-n)-cycloalkyl denotes a saturated mono-, bi-, tri- orspirocarbocyclic group with 3 to n C atoms. Examples of such groupsinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclononyl, cyclododecyl, bicyclo[3.2.1. ]octyl,spiro[4.5]decyl, norpinyl, norbonyl, norcaryl, adamantyl, etc.Preferably, the term C₃₋₇-cycloalkyl includes saturated monocyclicgroups.

The term C_(5-n)-cycloalkenyl denotes a monounsaturated mono-, bi-, tri-or spirocarbocyclic group with 5 to n C atoms. Examples of such groupsinclude cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl,cyclononenyl, etc.

The term C_(3-n)-cycloalkylcarbonyl denotes a C_(3-n)-cycloalkyl-C(═O)group, wherein C_(3-n)-cycloalkyl is defined as above.

The term aryl denotes a carbocyclic, aromatic ring system, such as forexample phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl,fluorenyl, indenyl, pentalenyl, azulenyl, biphenylenyl, etc. Aparticularly preferred meaning of “aryl” is phenyl.

The term cyclo-C₃₋₇-alkyleneimino denotes a 4- to 7-membered ring whichhas 3 to 7 methylene units as well as an imino group, the bond to therest of the molecule being made via the imino group.

The term cyclo-C₃₋₇-alkyleneimino-carbonyl denotes acyclo-C₃₋₇-alkyleneimino ring as defined hereinbefore which is linked toa carbonyl group via the imino group.

The term heteroaryl used in this application denotes a heterocyclic,aromatic ring system which comprises in addition to at least one C atomone or more heteroatoms selected from N, O and/or S. Examples of suchgroups are furanyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, 1,3,5-triazolyl,pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl,1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl,thiadiazinyl, indolyl, isoindolyl, benzofuranyl,benzothiophenyl(thianaphthenyl), indazolyl, benzimidazolyl,benzthiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, purinyl,quinazolinyl, quinozilinyl, quinolinyl, isoquinolinyl, quinoxalinyl,naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyl,etc. The term heteroaryl also comprises the partially hydrogenatedheterocyclic, aromatic ring systems, particularly those listed above.Examples of such partially hydrogenated ring systems are2,3-dihydrobenzofuranyl, pyrolinyl, pyrazolinyl, indolinyl,oxazolidinyl, oxazolinyl, oxazepinyl, etc. Particularly preferably,heteroaryl denotes a heteroaromatic mono- or bicyclic ring system.

Terms such as aryl-C_(1-n)-alkyl, heteroaryl-C_(1-n)-alkyl, etc. referto C_(1-n)-alkyl, as defined above, which is substituted with an aryl orheteroaryl group.

Many of the terms given above may be used repeatedly in the definitionof a formula or group and in each case have one of the meanings givenabove, independently of one another.

The term “unsaturated carbocyclic group” or “unsaturated heterocyclicgroup”, as used particularly in the definition of the group Cy,comprises, in addition to the totally unsaturated groups, thecorresponding, only partially unsaturated groups, particularly the mono-and diunsaturated groups.

The term “optionally substituted” used in this application indicatesthat the group thus designated is either unsubstituted or mono- orpolysubstituted by the substituents specified. If the group in questionis polysubstituted, the substituents may be identical or different.

The H atom of any carboxy group present or an H atom (imino or aminogroup) bonded to an N atom may in each case be replaced by a group whichcan be cleaved in vivo. By a group which can be cleaved in vivo from anN atom is meant for example a hydroxy group, an acyl group such as thebenzoyl or pyridinoyl group or a C₁₋₁₆-alkanoyl group such as theformyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, anallyloxycarbonyl group, a C₁₋₁₆-alkoxycarbonyl group such as themethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, tert.butoxycarbonyl, pentoxycarbonyl, hexyloxycarbonyl,octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl,undecyloxycarbonyl, dodecyloxycarbonyl or hexadecyloxycarbonyl group, aphenyl-C₁₋₆-alkoxycarbonyl group such as the benzyloxycarbonyl,phenylethoxycarbonyl or phenylpropoxycarbonyl group, aC₁₋₃-alkylsulphonyl-C₂₋₄-alkoxycarbonyl,C₁₋₃-alkoxy-C₂₋₄-alkoxy-C₂₋₄-alkoxycarbonyl orR_(e)CO—O—(R_(f)CR_(g))—O—CO group wherein

-   -   R_(e) denotes a C₁₋₈-alkyl, C₅₋₇-cycloalkyl, phenyl or        phenyl-C₁₋₃-alkyl group,    -   R_(f) denotes a hydrogen atom, a C₁₋₃-alkyl, C₅₋₇-cycloalkyl or        phenyl group and    -   R_(g) denotes a hydrogen atom, a C₁₋₃-alkyl or        R_(e)CO—O—(R_(f)CR_(g))—O group wherein R_(e) to R_(g) are as        hereinbefore defined,

while additionally the phthalimido group is a possibility for an aminogroup, and the above-mentioned ester groups may also be used as groupswhich can be converted into a carboxy group in vivo.

The residues and substituents described above may be mono- orpolysubstituted by fluorine as described. Preferred fluorinated alkylgroups are fluoromethyl, difluoromethyl and trifluoromethyl. Preferredfluorinated alkoxy groups are fluoromethoxy, difluoromethoxy andtrifluoromethoxy. Preferred fluorinated alkylsulphinyl andalkylsulphonyl groups are trifluoromethylsulphinyl andtrifluoromethylsulphonyl.

The compounds of general formula I according to the invention may haveacid groups, predominantly carboxyl groups, and/or basic groups such ase.g. amino functions. Compounds of general formula I may therefore bepresent as internal salts, as salts with pharmaceutically useableinorganic acids such as hydrochloric acid, sulphuric acid, phosphoricacid, sulphonic acid or organic acids (such as for example maleic acid,fumaric acid, citric acid, tartaric acid or acetic acid) or as saltswith pharmaceutically useable bases such as alkali or alkaline earthmetal hydroxides or carbonates, zinc or ammonium hydroxides or organicamines such as e.g. diethylamine, triethylamine, triethanolamine interalia.

The compounds according to the invention may be obtained using methodsof synthesis which are known in principle. Preferably the compounds areobtained by the methods of preparation according to the invention, whichare described more fully hereinafter.

The two reaction plans A and B which follow illustrate the synthesis ofthe compounds A.5 and B.5 according to the invention, wherein R¹, R², X,Y, Z, W, A and B have one of the meanings described hereinbefore. Inreaction plan A the group Y denotes an aryl or heteroaryl group, whereasin reaction plan B the group A denotes an aryl or heteroaryl group. Haldenotes chlorine, bromine or iodine, particularly bromine or iodine,particularly preferably iodine.

According to reaction plan A the halogen compound A.1 is reacted withthe alkyne compound A.2 in a molar ratio of about 1.5:1 to 1:1.5 under aprotective gas atmosphere in the presence of a suitable palladiumcatalyst, a suitable base and copper(I)iodide in a suitable solvent.

A preferred amount of copper(I)iodide is in the range from 1 to 15 mol%, particularly from 5 to 10 mol % based on the educt A.1.

Suitable palladium catalysts are for example Pd(PPh₃)₄, Pd₂(dba)₃,Pd(OAc)₂, Pd(PPh₃)₂Cl₂, Pd(CH₃CN)₂Cl₂, Pd(dppf)Cl₂. The palladiumcatalyst is preferably used in an amount of from 1 to 15 mol %,particularly 5 to 10 mol % based on the educt A.1.

Suitable bases are particularly amines, such as for exampletriethylamine or ethyldiisopropylamine, as well as Cs₂CO₃. The base ispreferably used in at least equimolar amounts based on the educt A.1, inexcess or as the solvent as well. Other suitable solvents aredimethylformamide or ethers, such as for example tetrahydrofuran,including the mixtures thereof. The reaction is carried out over aperiod of about 2 to 24 hours in a temperature range from about 20 to90° C.

The alkyne compound A.3 obtained is reacted directly or after previouspurification with methanesulphonic acid chloride to form themethanesulphonate derivative A.4. The reaction conditions required areknown as such to the skilled man. Advantageous solvents are halogenatedhydrocarbons, such as for example dichloromethane. Suitable reactiontemperatures are normally in the range from 0 to 30° C.

The reaction solution containing the methanesulphonate derivative A.4,or the purified methanesulphonate derivative A.4, dissolved in asuitable solvent, is reacted with an amine H—NR¹R² to obtain the endproduct A.5 and then optionally purified. If the amine H—NR¹R² hasanother primary or secondary amine function, this is advantageouslyprotected beforehand by a protective group which can be cleaved againafter the reaction has ended, using methods known from the literature.The product thus obtained may for example be converted into the saltform by reaction with a corresponding acid. A preferred molar ratio ofthe derivative A.4 to the amine compound is in the range from 1.5:1 to1:1.5. Suitable solvents are dimethylformamide or ether, such as forexample tetrahydrofuran, including the mixtures thereof.

The reaction to obtain the product A.5 is advantageously carried out ina temperature range of about 20 to 90° C.

Reaction Plan A:

According to reaction plan B the halogen compound B.2 is reacted withthe alkyne compound B.1 in a molar ratio of about 1.5:1 to 1:1.5 under aprotective gas atmosphere in the presence of a suitable palladiumcatalyst, a suitable base and copper(I)iodide in a suitable solvent.Details of suitable reaction conditions, including catalysts, bases andsolvents, may be found in the description of reaction plan A.

The alkyne compound B.3 obtained is reacted with methanesulphonic acidchloride directly or after previous purification, to form themethanesulphonate derivative B.4. The reaction conditions required canagain be found in the description relating to Reaction plan A.

The reaction solution containing the methanesulphonate derivative B.4,or the purified methanesulphonate derivative B.4, dissolved in asuitable solvent, is reacted with an amine H—NR¹R² to obtain the endproduct B.5 and then optionally purified. Once again, the remarksrelating to Reaction plan A apply.

Reaction Plan B:

According to the additional reaction plan C the halogen compound C.1 isreacted directly with the alkyne compound C.2 in a molar ratio of about1.5:1 to 1:1.5 under a protective gas atmosphere in the presence of asuitable palladium catalyst, a suitable base and copper(I)iodide in asuitable solvent to obtain the product C.3. Details of suitable reactionconditions, including catalysts, bases and solvents, may be found in thedescription of reaction plan A.

Reaction Plan C:

An alternative method of synthesis is shown in reaction plan D.According to this the halogen compound D.2 is reacted directly with thealkyne compound D.1 in a molar ratio of about 1.5:1 to 1:1.5 under aprotective gas atmosphere in the presence of a suitable palladiumcatalyst, a suitable base and copper(I)iodide in a suitable solvent toform the product D.3. Once again, details of suitable reactionconditions, including catalysts, bases and solvents, may be found in thedescription of reaction plan A.

Reaction Plan D:

The reactions according to plans A, B, C and D may be carried out toparticular advantage with the corresponding iodine compounds A.1, B.2,C.1 and D.2. In the event that Hal denotes bromine in compounds A.1,B.2, C.1 and D.2, it is advantageous to convert it into thecorresponding iodine compound beforehand. A particularly advantageousprocess is the Aryl-Finkelstein reaction (Klapars, Artis; Buchwald,Stephen L. Copper-Catalyzed Halogen Exchange in Aryl Halides: AnAromatic Finkelstein Reaction. Journal of the American Chemical Society(2002), 124(50), 14844-14845). Thus for example the halogen compoundA.1, B.2, C.1 bzw. D.2 may be reacted with sodium iodide in the presenceof N,N′-dimethyl-ethylenediamine and copper(I)iodide in a suitablesolvent to obtain the corresponding iodine compound. An advantageousmolar ratio of the halogen compound to sodium iodide is 1:1.8 to 1:2.3.N,N′-dimethyl-ethylenediamine is advantageously used in a molar ratio of10 to 30 mol % based on the halogen compound A.1, B.2, C.1 or D.2.Preferred amounts of copper(I)iodide are in the range from 5 to 20 mol %based on the halogen compound A.1, B.2, C.1 or D.2. A suitable solventis 1,4-dioxane, for example. Suitable reaction temperatures are in therange from about 20 to 110° C. The reaction is substantially completeafter 2 to 72 hours.

The compounds according to the invention may advantageously also beobtained using methods described in the following Examples, which mayalso be combined with methods known to the skilled man from theliterature, for example.

Stereoisomeric compounds of formula (I) may be separated in principle byconventional methods. The diastereomers may be separated on the basis oftheir different physico-chemical properties, e.g. by fractionalcrystallisation from suitable solvents, by high pressure liquid orcolumn chromatography, using chiral or preferably non-chiral stationaryphases.

Racemates covered by general formula (I) may be separated for example byHPLC on suitable chiral stationary phases (e.g. Chiral AGP, ChiralpakAD). Racemates which contain a basic or acidic function can also beseparated via the diastereomeric, optically active salts which areproduced on reacting with an optically active acid, for example (+) or(−)-tartaric acid, (+) or (−)-diacetyl tartaric acid, (+) or(−)-monomethyl tartrate or (+)-camphorsulphonic acid, or an opticallyactive base, for example with (R)-(+)-1-phenylethylamine,(S)-(−)-1-phenylethylamine or (S)-brucine.

According to a conventional method of separating isomers, the racemateof a compound of general formula (I) is reacted with one of theabove-mentioned optically active acids or bases in equimolar amounts ina solvent and the resulting crystalline, diastereomeric, opticallyactive salts thereof are separated using their different solubilities.This reaction may be carried out in any type of solvents provided thatthey show sufficient differences in terms of the solubility of thesalts. Preferably, methanol, ethanol or mixtures thereof, for example ina ratio by volume of 50:50, are used. Then each of the optically activesalts is dissolved in water, carefully neutralised with a base such assodium carbonate or potassium carbonate, or with a suitable acid, e.g.with dilute hydrochloric acid or aqueous methanesulphonic acid, and inthis way the corresponding free compound is obtained in the (+) or (−)form.

The (R) or (S) enantiomer alone or a mixture of two optically activediastereomeric compounds covered by general formula I may also beobtained by performing the syntheses described above with a suitablereaction component in the (R) or (S) configuration.

As already mentioned, the compounds of formula (I) may be converted intothe salts thereof, particularly for pharmaceutical use into thephysiologically and pharmacologically acceptable salts thereof. Thesesalts may be present on the one hand as physiologically andpharmacologically acceptable acid addition salts of the compounds offormula (I) with inorganic or organic acids. On the other hand, in thecase of acidically bound hydrogen, the compound of formula (I) may alsobe converted by reaction with inorganic bases into physiologically andpharmacologically acceptable salts with alkali or alkaline earth metalcations as counter-ion. The acid addition salts may be prepared, forexample, using hydrochloric acid, hydrobromic acid, sulphuric acid,phosphoric acid, methanesulphonic acid, ethanesulphonic acid,toluenesulphonic acid, benzenesulphonic acid, acetic acid, fumaric acid,succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.Moreover, mixtures of the above mentioned acids may be used. To preparethe alkali and alkaline earth metal salts of the compound of formula (I)with acidically bound hydrogen the alkali and alkaline earth metalhydroxides and hydrides are preferably used, while the hydroxides andhydrides of the alkali metals, particularly sodium and potassium arepreferred and sodium and potassium hydroxide are most preferred.

The compounds according to the present invention, including thephysiologically acceptable salts, are effective as antagonists of theMCH receptor, particularly the MCH-1 receptor, and exhibit good affinityin MCH receptor binding studies. Pharmacological test systems forMCH-antagonistic properties are described in the following experimentalsection.

As antagonists of the MCH receptor the compounds according to theinvention are advantageously suitable as pharmaceutical activesubstances for the prevention and/or treatment of symptoms and/ordiseases caused by MCH or causally connected with MCH in some other way.Generally the compounds according to the invention have low toxicity,they are well absorbed by oral route and have an intracerebraltransitivity, particularly brain accessibility.

Therefore, MCH antagonists which contain at least one compound accordingto the invention, are particularly suitable in mammals, such as forexample rats, mice, guinea pigs, hares, dogs, cats, sheep, horses, pigs,cattle, monkeys and also humans, for the treatment and/or prevention ofsymptoms and/or diseases which are caused by MCH or are otherwisecausally connected with MCH.

Diseases caused by MCH or otherwise causally connected with MCH areparticularly metabolic disorders, such as for example obesity, andeating disorders, such as for example bulimia, including bulimianervosa. The indication obesity includes in particular exogenic obesity,hyperinsulinaemic obesity, hyperplasmic obesity, hyperphyseal adiposity,hypoplasmic obesity, hypothyroid obesity, hypothalamic obesity,symptomatic obesity, infantile obesity, upper body obesity, alimentaryobesity, hypogonadal obesity and central obesity. This range ofindications also includes cachexia, anorexia and hyperphagia.

Compounds according to the invention may, in particular, be suitable forreducing hunger, curbing appetite, controlling eating behaviour and/orpromoting a feeling of satiety.

In addition, the diseases caused by MCH or otherwise causally connectedwith MCH also include hyperlipidaemia, cellulitis, fat accumulation,malignant mastocytosis, systemic mastocytosis, emotional disorders,affectivity disorders, depression, anxiety states, sleep disoreders,reproductive disorders, sexual disorders, memory disorders, epilepsy,forms of dementia and hormonal disorders.

Compounds according to the invention are also suitable as activesubstances for the prevention and/or treatment of other illnesses and/ordisorders, particularly those which accompany obesity, such as, forexample, diabetes, diabetes mellitus, especially type II diabetes,hyperglycaemia, particularly chronic hyperglycaemia, complications ofdiabetes including diabetic retinopathy, diabetic neuropathy, diabeticnephropathy, etc., insulin resistance, pathological glucose tolerance,encephalorrhagia, cardiac insufficiency, cardiovascular diseases,particularly arteriosclerosis and high blood pressure, arthritis andgonitis.

MCH antagonists and formulations according to the invention mayadvantageously be used in combination with a dietary therapy, such asfor example a dietary diabetes treatment, and exercise.

Another range of indications for which the compounds according to theinvention are advantageously suitable is the prevention and/or treatmentof urinary disorders, such as for example urinary incontinence,overactive bladder, urgency, nycturia and enuresis, while the overactivebladder and urgency may or may not be connected with benign prostatichyperplasia.

The dosage required to achieve such an effect is conveniently, byintravenous or subcutaneous route, 0.001 to 30 mg/kg of body weight,preferably 0.01 to 5 mg/kg of body weight, and by oral or nasal route orby inhalation, 0.01 to 50 mg/kg of body weight, preferably 0.1 to 30mg/kg of body weight, in each case once to three times a day.

For this purpose, the compounds of formula I prepared according to theinvention may be formulated, optionally together with other activesubstances as described hereinafter, together with one or more inertconventional carriers and/or diluents, e.g. with corn starch, lactose,glucose, microcrystalline cellulose, magnesium stearate,polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol,water/glycerol, water/sorbitol, water/polyethylene glycol, propyleneglycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substancessuch as hard fat or suitable mixtures thereof, to produce conventionalgalenic preparations such as plain or coated tablets, capsules, powders,granules, solutions, emulsions, syrups, aerosols for inhalation,ointments or suppositories.

In addition to pharmaceutical compositions the invention also coverscompositions containing at least one alkyne compound according to theinvention and/or a salt according to the invention optionally togetherwith one or more physiologically acceptable excipients. Suchcompositions may also be foods, for example, which may be solid orliquid, in which the compound according to the invention isincorporated.

For the above mentioned combinations it is possible to use as additionalactive substances particularly those which for example potentiate thetherapeutic effect of an MCH antagonist according to the invention interms of one of the indications mentioned above and/or which make itpossible to reduce the dosage of an MCH antagonist according to theinvention. Preferably one or more additional active substances areselected from among

-   -   active substances for the treatment of diabetes,    -   active substances for the treatment of diabetic complications,    -   active substances for the treatment of obesity, preferably other        than MCH antagonists,    -   active substances for the treatment of high blood pressure,    -   active substances for the treatment of hyperlipidaemia,        including arteriosclerosis,    -   active substances for the treatment of arthritis,    -   active substances for the treatment of anxiety states,    -   active substances for the treatment of depression.

The above mentioned categories of active substances will now beexplained in more detail by means of examples.

Examples of active substances for the treatment of diabetes are insulinsensitisers, insulin secretion accelerators, biguanides, insulins,α-glucosidase inhibitors, β3 adreno-receptor agonists.

-   -   Insulin sensitisers include pioglitazone and its salts        (preferably hydrochloride), troglitazone, rosiglitazone and its        salts (preferably maleate), JTT-501, GI-262570, MCC-555, YM-440,        DRF-2593, BM-13-1258, KRP-297, R-119702, GW-1929.    -   Insulin secretion accelerators include sulphonylureas, such as        for example tolbutamide, chloropropamide, tolzamide,        acetohexamide, glyclopyramide and its ammonium salts,        glibenclamide, gliclazide, glimepiride. Further examples of        insulin secretion accelerators are repaglinide, nateglinide,        mitiglinide (KAD-1229) and JTT-608.    -   Biguanides include mefformin, buformin and phenformin.    -   Insulins include those obtained from animals, particularly        cattle or pigs, semisynthetic human insulins which are        synthesised enzymatically from insulin obtained from animals,        human insulin obtained by genetic engineering, e.g. from        Escherichia coli or yeasts. Moreover, the term insulin also        includes insulin-zinc (containing 0.45 to 0.9 percent by weight        of zinc) and protamine-insulin-zinc obtainable from zinc        chloride, protamine sulphate and insulin. Insulation may also be        obtained from insulin fragments or derivatives (for example        INS-1, etc.).    -   Insulin may also include different kinds, e.g. with regard to        the onset time and duration of effect (“ultra immediate action        type”, “immediate action type”, “two phase type”, “intermediate        type”, “prolonged action type”, etc.), which are selected        depending on the pathological condition of the patient.    -   α-Glucosidase inhibitors include acarbose, voglibose, miglitol,        emiglitate.    -   β₃ Adreno receptor agonists include AJ-9677, BMS-196085,        SB-226552, AZ40140.    -   Active substances for the treatment of diabetes other than those        mentioned above include ergoset, pramlintide, leptin,        BAY-27-9955 as well as glycogen phosphorylase inhibitors,        sorbitol dehydrogenase inhibitors, protein tyrosine phosphatase        1B inhibitors, dipeptidyl protease inhibitors, glipazid,        glyburide.

Active substances for the treatment of diabetic complications includefor example aldose reductase inhibitors, glycation inhibitors andprotein kinase C inhibitors.

-   -   Aldose reductase inhibitors are for example tolrestat,        epalrestat, imirestat, zenarestat, SNK-860, zopolrestat,        ARI-50i, AS-3201.    -   An example of a glycation inhibitor is pimagedine.    -   Protein Kinase C inhibitors are for example NGF, LY-333531.    -   Active substances other than those mentioned above for the        treatment of diabetic complications include alprostadil,        thiapride hydrochloride, cilostazol, mexiletine hydrochloride,        ethyl eicosapentate, memantine, pimagedine (ALT-711).

Active substances for the treatment of obesity, preferably other thanMCH antagonists, include lipase inhibitors and anorectics.

-   -   A preferred example of a lipase inhibitor is orlistat.    -   Examples of preferred anorectics are phentermine, mazindol,        dexfenfluramine, fluoxetine, sibutramine, baiamine,        (S)-sibutramine, SR-141716, NGD-95-1.    -   Active substances other than those mentioned above for the        treatment of obesity include lipstatin.    -   Moreover for the purposes of this application the active        substance group of anti-obesity active substances also includes        the anorectics, of which the β₃ agonists, thyromimetic active        substances and NPY antagonists should be emphasised. The scope        of the anti-obesity or anorectic active substances which are        preferred here is indicated by the following additional list, by        way of example: phenylpropanolamine, ephedrine, pseudoephedrine,        phentermine, a cholecystokinin-A (hereinafter referred to as        CCK-A) agonist, a monoamine reuptake inhibitor (such as for        example sibutramine), a sympathomimetic active substance, a        serotonergic active substance (such as for example        dexfenfluramine or fenfluramine), a dopamine antagonist (such as        for example bromocriptine), a melanocyte-stimulating hormone        receptor agonist or mimetic, an analogue of        melanocyte-stimulating hormone, a cannabinoid receptor        antagonist, an MCH antagonist, the OB protein (hereinafter        referred to as leptin), a leptin analogue, a leptin receptor        agonist, a galanine antagonist, a GI lipase inhibitor or reducer        (such as for example orlistat). Other anorectics include        bombesin agonists, dehydroepiandrosterone or its analogues,        glucocorticoid receptor agonists and antagonists, orexin        receptor antagonists, urocortin binding protein antagonists,        agonists of the Glucagon-like Peptide-1 receptor, such as for        example exendin and ciliary neurotrophic factors, such as for        example axokine.

Active substances for the treatment of high blood pressure includeinhibitors of angiotensin converting enzyme, calcium antagonists,potassium channel openers and angiotensin II antagonists.

-   -   Inhibitors of angiotensin converting enzyme include captopril,        enalapril, alacepril, delapril (hydrochloride), lisinopril,        imidapril, benazepril, cilazapril, temocapril, trandolapril,        manidipine (hydrochloride).    -   Examples of calcium antagonists are nifedipine, amlodipine,        efonidipine, nicardipine.    -   Potassium channel openers include levcromakalim, L-27152,        AL0671, NIP-121.    -   Angiotensin II antagonists include telmisartan, losartan,        candesartan cilexetil, valsartan, irbesartan, CS-866, E4177.

Active substances for the treatment of hyperlipidaemia, includingarteriosclerosis, include HMG-CoA reductase inhibitors, fibratecompounds.

-   -   HMG-CoA reductase inhibitors include pravastatin, simvastatin,        lovastatin, atorvastatin, fluvastatin, lipantil, cerivastatin,        itavastatin, ZD-4522 and the salts thereof.    -   Fibrate compounds include bezafibrate, clinofibrate, clofibrate        and simfibrate.

Active substances for the treatment of arthritis include ibuprofen.

Active substances for the treatment of anxiety states includechlordiazepoxide, diazepam, oxazolam, medazepam, cloxazolam, bromazepam,lorazepam, alprazolam, fludiazepam.

Active substances for the treatment of depression include fluoxetine,fluvoxamine, imipramine, paroxetine, sertraline.

The dosage for these active substances is conveniently 1/5 of the lowestnormal recommended dose up to 1/1 of the normal recommended dose.

In another embodiment the invention also relates to the use of at leastone alkyne compound according to the invention and/or a salt accordingto the invention for influencing the eating behaviour of a mammal. Thisuse is based particularly on the fact that compounds according to theinvention may be suitable for reducing hunger, curbing appetite,controlling eating behaviour and/or promoting a feeling of satiety. Theeating behaviour is advantageously influenced in such a way as to reducefood intake. Therefore, the compounds according to the invention areadvantageously used for reducing body weight. A further use according tothe invention is the prevention of increases in body weight, for examplein people who have previously taken steps to reduce their weight and arethen interested in maintaining their reduced body weight. According tothis embodiment it is preferably a non-therapeutic use. Such anon-therapeutic use may be a cosmetic use, for example for altering theouter appearance, or an application for improving the general feeling ofwellbeing. The compounds according to the invention are preferably usedin a non-therapeutic capacity for mammals, particularly humans, who haveno diagnosed disorders of eating behaviour, no diagnosed obesity,bulimia, diabetes and/or no diagnosed urinary problems, particularlyurinary incontinence. Preferably the compounds according to theinvention are suitable for non-therapeutic use in humans whose body massindex (BMI=body mass index), which is defined as the body weightmeasured in kilograms divided by the height (in metres) squared, is lessthan 30, particularly less than 25.

The Examples that follow are intended to illustrate the invention:

Preliminary Remarks

As a rule, IR, ¹H-NMR and/or mass spectra have been obtained for thecompounds prepared. Unless otherwise stated the R_(f) values aredetermined using ready-made silica gel 60 TLC plates F₂₅₄ (E. Merck,Darmstadt, Item no. 1.05714) without chamber saturation. The R_(f)values obtained under the name Alox are determined using ready-madealuminium oxide 60 F₂₅₄ TLC plates (E. Merck, Darmstadt, Item no.1.05713) without chamber saturation. The ratios given for the eluantsrelate to units by volume of the solvent in question. The units byvolume for NH₃ relate to a concentrated solution of NH₃ in water. Silicagel made by Millipore (MATREX™, 35-70 my) is used for chromatographicpurification. Alox (E. Merck, Darmstadt, aluminium oxide 90standardised, 63-200 μm, Item no. 1.01097.9050) is used forchromatographic purification. The HPLC data given are measured under thefollowing parameters:

Analytical columns: Zorbax column (Agilent Technologies), SB (StableBond)—C18; 3.5 μm; 4.6×75 mm; column temperature: 30° C.; flow: 0.8mL/min; injection volume: 5 μL; detection at 254 nm (methods A and B)

Symmetry 300 (Waters), 3.5 μm; 4.6×75 mm; column temperature: 30° C.;flow: 0.8 mL/min; injection volume: 5 μL; detection at 254 nm (method C)

-   method A: water:acetonitrile:formic acid 9:1:0.01 to 1:9:0.01 over 9    min-   method B: water:acetonitrile:formic acid 9:1:0.01 to 1:9:0.01 over 4    min, then 6 min 1:9:0.01-   method C: water:acetonitrile:formic acid 9:1:0.01 to 1:9:0.01 over 4    min, then 6 min 1:9:0.01

Preparative column: Zorbax column (Agilent Technologies), SB (StableBond)—C18; 3.5 μm; 30×100 mm; column temperature: ambient temperature;flow: 30 mL/min; detection at 254 nm.

In preparative HPLC purifications, as a rule, the same gradients areused as were used to raise the analytical HPLC data.

The products are collected under mass control, the fractions containingproduct are combined and freeze-dried.

If there is no specific information as to the configuration, it is notclear whether there are pure enantiomers or whether partial or eventotal racemisation has taken place.

The following abbreviations are used above and hereinafter:

CDI carbonyldiimidazole cyc cyclohexane DCM dichloromethane DMFdimethylformamide DMSO dimethylsulphoxide dppf1,1′-bis(diphenylphosphino)ferrocene EtOAc ethyl acetate EtOH ethanol Fpmelting point i.vac. in vacuo MeOH methanol PE petroleum ether PPh₃triphenylphosphane RT ambient temperature TBAFtetrabutylammoniumfluoride trihydrate THF tetrahydrofuranGeneral Experimental Method I (Sonogashira Couplings)

Under an argon atmosphere, a suitable palladium catalyst (e.g. Pd(PPh₃)₄(5 mol %), Pd(PPh₃)₂Cl₂ (5 mol %), Pd(CH₃CN)Cl₂ (5 mol %) or Pd(dppf)Cl₂(5 or 10 mol %)), a suitable base (e.g. caesium carbonate (1.5 eq) ortriethylamine (1.5 eq.)) and CuI (5 or 10 mol %) are added successivelyto a solution of the aryl or heteroaryl iodide or bromide (1.0 eq) andthe alkyne (1.05 eq) in THF or DMF. The reaction solution is stirred atRT to 90° C. for between 2-24 h, filtered and the solvent is eliminatedi.vac. Further purification is carried out by column chromatography orby purification using HPLC-MS.

General Experimental Method II (Bromine-iodine Exchange)

NaI (2.0 eq), N,N′-dimethyl-ethylenediamine (0.2 eq.) and CuI (0.1 eq.)are added successively to a solution of the aryl or heteroaryl bromide(1.0 eq.) in 1,4-dioxane under argon. The reaction is stirred for 2-72 hat RT to 110° C. and then diluted with NH₃. The aqueous phase isextracted with DCM, the organic phase is dried over MgSO₄ and thesolvent is eliminated i.vac. If necessary further purification iscarried out by column chromatography.

EXAMPLE 1Diethyl-(2-{4-[5-(4-methoxy-phenyl)-pyridin-2-ylethynyl]-phenoxy}-ethyl)-amine

1a [2-(4-bromo-phenoxy)-ethyl]-diethyl-amine

A suspension of 31.4 g (178 mmol) 4-bromophenol, 30.6 g (178 mmol)(2-chloro-ethyl)-diethyl-amine (used as the hydrochloride) and 61.5 g(445 mmol) K₂CO₃ in 300 mL DMF is heated to 80° C. for 8 h. The solventis evaporated down i.vac., the residue combined with water, the aqueousphase exhaustively extracted with EtOAc, the combined organic phaseswashed with water again and dried over MgSO₄. After the desiccant andsolvent have been eliminated the residue is purified by chromatography(silica gel, EtOAc/MeOH/NH₃ 90:10:1).

Yield: 28.0 g (58% of theory). C₁₂H₁₈BrNO (M=272.187). Calc.: molpeak(M+H)⁺: 272/274 Found: molpeak (M+H)⁺: 272/274. R_(f) value: 0.25(silica gel, EtOAc/MeOH/NH₃ 90:10:1).

1b diethyl-[2-(4-trimethylsilanylethynyl-phenoxy)-ethyl]-amine

Under a nitrogen atmosphere a mixture of 5.44 g (20 mmol)[2-(4-bromo-phenoxy)-ethyl]-diethyl-amine, 3.11 mL (22 mmol)ethynyl-trimethyl-silane, 462 mg (0.4 mmol)tetrakis-triphenylphosphane-palladium, 76 mg (0.4 mmol) CuI in 50 mLpiperidine is heated to 70° C. for 21 h. The solvent is distilled offi.vac., the residue is taken up in water, exhaustively extracted withEtOAc and dried over Na₂SO₄. After the desiccant and solvent have beeneliminated the residue is purified on silica gel (EtOAc/MeOH/NH₃95:5:0.5).

Yield: 1.4 g (24% of theory). C₁₇H₂₇NOSi (M=289.497). Calc.: molpeak(M+H)⁺: 290 Found: molpeak (M+H)⁺: 290. R_(f) value: 0.67 (silica gel,EtOAc/MeOH/NH₃ 95:5:0.5).

1c diethyl-[2-(4-ethynyl-phenoxy)-ethyl]-amine

Under a nitrogen atmosphere a solution of 1.4 g (4.8 mmol)diethyl-[2-(4-trimethylsilanylethynyl-phenoxy)-ethyl]-amine in 50 mL THFis combined with 1.68 g (5.3 mmol) TBAF and stirred overnight at RT. Thesolvent is distilled off i.vac., the residue is taken up in water,exhaustively extracted with EtOAc and dried over Na₂SO₄. After thedesiccant and solvent have been eliminated the residue is purified onsilica gel (EtOAc/MeOH 95:5).

Yield: 0.5 g (47% of theory). C₁₄H₁₉NO (M=217.314). Calc.: molpeak(M+H)⁺: 218 Found: molpeak (M+H)⁺: 218. R_(f) value: 0.46 (silica gel,EtOAc/MeOH/NH₃ 95:5:0.5).

1d {2-[4-(5-bromo-pyridin-2-ylethynyl)-phenoxy]-ethyl}-diethyl-amine

A mixture of 500 mg (2.30 mmol)diethyl-[2-(4-ethynyl-phenoxy)-ethyl]-amine, 545 mg (2.30 mmol)2,5-dibromopyridine, 161 mg (0.23 mmol)tetrakis-triphenylphosphane-palladium, 13 mg (0.07 mmol) CuI, 2 mLethyldiisopropylamine and 2 mL diisopropylamine in 50 mL DMF is heatedfor 20 h at 100° C. under a nitrogen atmosphere. The solvent isdistilled off i.vac., the residue is taken up in water, exhaustivelyextracted with EtOAc and dried over Na₂SO₄. After the desiccant andsolvent have been eliminated the residue is purified on silica gel(EtOAc/MeOH/NH₃ 95:5:0.5).

Yield: 200 mg (23% of theory). C₁₉H₂₁BrN₂O (M=373.296). Calc.: molpeak(M+H)⁺: 373/375 Found: molpeak (M+H)⁺: 373/375. R_(f) value: 0.50(silica gel, EtOAc/MeOH/NH₃ 90:10:1).

1ediethyl-(2-{4-[5-(4-methoxy-phenyl)-pyridin-2-ylethynyl]-phenoxy}-ethyl)-amine

A mixture of 200 mg (0.54 mmol){2-[4-(5-bromo-pyridin-2-ylethynyl)-phenoxy]-ethyl}-diethyl-amine, 163mg (1.07 mmol) 4-methoxy-phenylboric acid, 31 mg (0.03 mmol)tetrakis-triphenylphosphane-palladium and 0.27 mL of a 2 M aqueousNa₂CO₃ solution in 5 mL 1,4-dioxane is heated for 20 h at 110° C. undera nitrogen atmosphere. The solvent is distilled off i.vac., the residueis taken up in water, exhaustively extracted with EtOAc and dried overNa₂SO₄. After the desiccant and solvent have been eliminated the residueis purified on silica gel (EtOAc/MeOH/NH₃ 95:5:0.5). The productfractions are evaporated down, the residue is triturated with diethylether, suction filtered and washed with diisopropylether.

Yield: 30 mg (14% of theory). C₂₆H₂₈N₂O₂ (M=400.525). Calc.: molpeak(M+H)⁺: 401 Found: molpeak (M+H)⁺: 401. R_(f) value: 0.46 (silica gel,EtOAc/MeOH/NH₃ 95:5:0.5).

EXAMPLE 1.1diethyl-(2-{4-[5-(2-methoxy-phenyl)-pyridin-2-ylethynyl]-phenoxy}-ethyl)-amine

The product is obtained analogously to Example 1e from 200 mg (0.54mmol) {2-[4-(5-bromo-pyridin-2-ylethynyl)-phenoxy]-ethyl}-diethyl-amineand 163 mg (1.07 mmol) 2-methoxy-phenylboric acid.

Yield: 40 mg (14% of theory). C₂₆H₂₈N₂O₂ (M=400.525). Calc.: molpeak(M+H)⁺: 401 Found: molpeak (M+H)⁺: 401. R_(f) value: 0.23 (silica gel,EtOAc/MeOH/NH₃ 95:5:0.5).

EXAMPLE 1.2(2-{4-[5-(4-ethoxy-phenyl)-pyridin-2-ylethynyl]-phenoxy}-ethyl)-diethyl-amine

The product is obtained analogously to Example 1e from 200 mg (0.54mmol) {2-[4-(5-bromo-pyridin-2-ylethynyl)-phenoxy]-ethyl}-diethyl-amineand 178 mg (1.07 mmol) 4-ethoxy-phenylboric acid.

Yield: 83 mg (37% of theory). C₂₇H₃₀N₂O₂ (M=414.552). Calc.: molpeak(M+H)⁺: 414 Found: molpeak (M+H)⁺: 414. R_(f) value: 0.26 (silica gel,EtOAc/MeOH/NH₃ 95:5:0.5).

EXAMPLE 1.3(2-{4-[5-(3,4-difluoro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-ethyl)-diethyl-amine

The product is obtained analogously to Example 1e from 200 mg (0.54mmol) {2-[4-(5-bromo-pyridin-2-ylethynyl)-phenoxy]-ethyl}-diethyl-amineand 169 mg (1.07 mmol) 3,4-difluoro-phenylboric acid.

Yield: 35 mg (16% of theory). C₂₅H₂₄F₂N₂O (M=406.480). Calc.: molpeak(M+H)⁺: 407 Found: molpeak (M+H)⁺: 407. R_(f) value: 0.34 (silica gel,EtOAc/MeOH/NH₃ 95:5:0.5).

EXAMPLE 1.4(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-ethyl)-diethyl-amine

The product is obtained analogously to Example 1e from 200 mg (0.54mmol) {2-[4-(5-bromo-pyridin-2-ylethynyl)-phenoxy]-ethyl}-diethyl-amineand 167 mg (1.07 mmol) 4-chloro-phenylboric acid.

Yield: 51 mg (24% of theory). C₂₅H₂₅ClN₂O (M=404.944). Calc.: molpeak(M+H)⁺: 405/407 Found: molpeak (M+H)⁺: 405/407. R_(f) value: 0.26(silica gel, EtOAc/MeOH/NH₃ 95:5:0.5).

EXAMPLE 1.5diethyl-(2-{4-[5-(4-methoxy-phenyl)-pyrimidine-2-ylethynyl]-phenoxy}-ethyl)-amine

The product is obtained analogously to Example 1d from 434 mg (2.0 mmol)diethyl-[2-(4-ethynyl-phenoxy)-ethyl]-amine and 441 mg (2.0 mmol)2-chloro-5-(4-methoxy-phenyl)-pyrimidine.

Yield: 100 mg (13% of theory). C₂₅H₂₇N₃O₂ (M=401.513). Calc.: molpeak(M+H)⁺: 402 Found: molpeak (M+H)⁺: 402. R_(f) value: 0.65 (silica gel,EtOAc/MeOH/NH₃ 90:10:1).

EXAMPLE 1.65-(4-chloro-phenyl)-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridine

1.6a 1-[2-(4-iodo-phenoxy)-ethyl]-pyrrolidine

A suspension of 22 g (100 mmol) 4-iodophenol, 17 g (100 mmol)1-(2-chloro-ethyl)-pyrrolidine (used as the hydrochloride) and 55.3 g(400 mmol) K₂CO₃ in 400 mL DMF is stirred for 48 h at RT. The solvent isevaporated down i.vac., the residue is combined with water, the aqueousphase exhaustively extracted with EtOAc, the combined organic phases arewashed with saturated, aqueous NaCl solution and dried over Na₂SO₄.After the desiccant and solvent have been eliminated the residue ispurified on silica gel (EtOAc/MeOH/NH₃ 85:15:1.5).

Yield: 18.0 g (57% of theory). C₁₂H₁₆INO (M=317.172). Calc.: molpeak(M+H)⁺: 318 Found: molpeak (M+H)⁺: 318. R_(f) value: 0.59 (silica gel,EtOAc/MeOH/NH₃ 80:20:2).

1.6b 1-[2-(4-trimethylsilanylethynyl-phenoxy)-ethyl]-pyrrolidine

Under a nitrogen atmosphere 7.0 mL (49.5 mmol) ethynyl-trimethyl-silaneis slowly added to a mixture of 14.3 g (45 mmol)1-[2-(4-iodo-phenoxy)-ethyl]-pyrrolidine, 1.04 g (0.9 mmol)tetrakis-triphenylphosphane-palladium and 171 mg (0.4 mmol) CuI in 140mL piperidine (exothermic reaction) and stirred for 30 minutes. Thesolvent is distilled off i.vac., the residue is taken up in water,exhaustively extracted with EtOAc and dried over Na₂SO₄. After thedesiccant and solvent have been eliminated the residue is purified onsilica gel (EtOAc/MeOH/NH₃ 95:5:0.5).

Yield: 12.8 g (99% of theory). C₁₇H₂₅NOSi (M=287.481). Calc.: molpeak(M+H)⁺: 288 Found: molpeak (M+H)⁺: 288. R_(f) value: 0.42 (silica gel,EtOAc/MeOH/NH₃ 90:10:1).

1.6c 1-[2-(4-ethynyl-phenoxy)-ethyl]-pyrrolidine

Under a nitrogen atmosphere a solution of 12.8 g (44.5 mmol)1-[2-(4-trimethylsilanylethynyl-phenoxy)-ethyl]-pyrrolidine in 200 mLTHF is combined with 15.5 g (49.0 mmol) TBAF and stirred for 3 h at RT.The solvent is distilled off i.vac., the residue taken up in EtOAc, theorganic phase is washed with saturated, aqueous NaCl solution and driedover Na₂SO₄. After the desiccant and solvent have been eliminated theproduct is further reacted without any purification.

Yield: 9.6 g (100% of theory). C₁₄H₁₇NO (M=215.298). Calc.: molpeak(M+H)⁺: 216 Found: molpeak (M+H)⁺: 216. R_(f) value: 0.76 (silica gel,EtOAc/MeOH/NH₃ 80:20:2).

1.6d 5-bromo-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridine

A mixture of 9.6 g (44.6 mmol)1-[2-(4-ethynyl-phenoxy)-ethyl]-pyrrolidine, 10.6 g (44.6 mmol)2,5-dibromopyridine, 626 mg (0.9 mmol)tetrakis-triphenylphosphane-palladium, 170 mg (0.9 mmol) CuCl and 12.6mL diisopropylamine in 500 mL THF is heated for 3 h at 40° C. under anargon atmosphere. The solvent is distilled off i.vac., the residue istaken up in EtOAc, the organic phase is washed with water and saturated,aqueous NaCl solution and dried over Na₂SO₄. After the desiccant andsolvent have been eliminated the residue is purified on silica gel(EtOAc/MeOH/NH₃ 90:10:1).

Yield: 8.9 g (54% of theory). C₁₉H₁₉BrN₂O (M=371.280) Calc.: molpeak(M+H)⁺: 371/373 Found: molpeak (M+H)⁺: 371/373. R_(f) value: 0.47(silica gel, EtOAc/MeOH/NH₃ 90:10:1).

1.6e5-(4-chloro-phenyl)-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridine

A mixture of 2.97 g (8.0 mmol)5-bromo-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridine, 2.50 g(16.0 mmol) 4-chloro-phenylboric acid, 462 mg (0.4 mmol)tetrakis-triphenylphosphane-palladium and 8.0 mL of a 2M aqueous Na₂CO₃solution in 100 mL 1,4-dioxane is heated for 4 h at 100° C. under anargon atmosphere. The solvent is distilled off i.vac., the residue isstirred with water/EtOAc (1/1,v/v), suction filtered through afibreglass filter, the organic phase is washed with saturated, aqueousNaCl solution and dried over Na₂SO₄. After the desiccant and solventhave been eliminated the residue is purified by chromatography (Alox,cyc/EtOAc 2:1). The product fractions are evaporated down, the residueis triturated with diethyl ether, suction filtered and washed withdiethyl ether.

Yield: 1.95 g (60% of theory). C₂₅H₂₃ClN₂O (M=402.928). Calc.: molpeak(M+H)⁺: 403/405 Found: molpeak (M+H)⁺: 403/405. R_(f) value: 0.47 (Alox,cyc/EtOAc 2:1).

EXAMPLE 1.75-(4-fluoro-phenyl)-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridine

The product is obtained analogously to Example 1.6e from 297 mg (0.8mmol) 5-bromo-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridineand 224 mg (1.6 mmol) 4-fluoro-phenylboric acid.

Yield: 37 mg (12% of theory). C₂₅H₂₃FN₂O (M=386.473). Calc.: molpeak(M+H)⁺: 387 Found: molpeak (M+H)⁺: 387. R_(f) value: 0.41 (Alox,cyc/EtOAc 2:1).

EXAMPLE 1.85-(4-bromo-phenyl)-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridine

The product is obtained analogously to Example 1.6e from 297 mg (0.8mmol) 5-bromo-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridineand 321 mg (1.6 mmol) 4-bromo-phenylboric acid. Purification is carriedout using neutral Alox (Merck aluminium oxide 90 standardised, 63-200my; cyc/EtOAc 4:1). The product thus obtained is recrystallised fromEtOH.

Yield: 40 mg (11% of theory). C₂₅H₂₃BrN₂O (M=447.379). Calc.: molpeak(M+H)⁺: 447/449 Found: molpeak (M+H)⁺: 447/449. R_(f) value: 0.45 (Alox,cyc/EtOAc 2:1).

EXAMPLE 1.92-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-5-(4-trifluoromethoxy-phenyl)-pyridine

The product is obtained analogously to Example 1.6e from 297 mg (0.8mmol) 5-bromo-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridineand 329 mg (1.6 mmol) 4-trifluoromethoxy-phenylboric acid. Purificationis carried out using neutral Alox (Merck aluminium oxide 90standardised, 63-200 my; cyc/EtOAc 4:1). The product thus obtained isstirred with n-hexane and suction filtered.

Yield: 190 mg (53% of theory). C₂₆H₂₃F₃N₂O₂ (M=452.481). Calc.: molpeak(M+H)⁺: 453 Found: molpeak (M+H)⁺: 453. R_(f) value: 0.46 (Alox,cyc/EtOAc 2:1).

EXAMPLE 1.102-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-5-(4-methoxy-phenyl)-pyridine

The product is obtained analogously to Example 1.9 from 297 mg (0.8mmol) 5-bromo-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridineand 243 mg (1.6 mmol) 4-methoxy-phenylboric acid.

Yield: 115 mg (53% of theory). C₂₆H₂₆N₂O₂ (M=398.509). Calc.: molpeak(M+H)⁺: 399 Found: molpeak (M+H)⁺: 399. R_(f) value: 0.30 (Alox,cyc/EtOAc 2:1).

EXAMPLE 1.112-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-5-(4-trifluoromethyl-phenyl)-pyridine

The product is obtained analogously to Example 1.9 from 297 mg (0.8mmol) 5-bromo-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridineand 304 mg (1.6 mmol) 4-trifluoromethyl-phenylboric acid.

Yield: 150 mg (43% of theory). C₂₆H₂₃F₃N₂O (M=436.481). Calc.: molpeak(M+H)⁺: 437 Found: molpeak (M+H)⁺: 437. R_(f) value: 0.45 (Alox,cyc/EtOAc 2:1).

EXAMPLE 25-(4-chloro-phenyl)-2-[4-(4-pyrrolidin-1-ylmethyl-phenyl)-but-1-ynyl]-pyridine

2a 1-(4-bromo-benzyl)-pyrrolidine

A solution of 12.5 g (50 mmol) 4-bromobenzylbromide is slowly addeddropwise to a solution of 4.52 mL (55 mmol) pyrrolidine and 10.3 mL (60mmol) ethyldiisopropylamine in 100 mL THF and stirred overnight at RT.The precipitate is filtered off and the solvent is eliminated i.vac. Theproduct is obtained as a light-brown liquid which is further reactedwithout purification.

Yield: 9.0 g (75% of theory). C₁₁H₁₄BrN (M=240.145), Calc.: molpeak(M+H)⁺: 241/243 Found: molpeak (M+H)⁺: 241/243. R_(f) value: 0.74(silica gel, EtOAc/MeOH/NH₃ 90:10:1).

2b 3-(4-pyrrolidin-1-ylmethyl-phenyl)-prop-2-yn-1-ol

A mixture of 4.8 g (20.0 mmol) 1-(4-bromo-benzyl)-pyrrolidine, 1.75 mL(30.0 mmol) propargylalcohol, 2.31 g (2.0 mmol)tetrakis-triphenylphosphane-palladium, 381 mg (2.0 mmol) CuI and 7.07 mLdiisopropylamine in 100 mL acetonitrile is heated for 14 h at 60° C.under an argon atmosphere. The solvent is distilled off i.vac., theresidue is taken up in water, exhaustively extracted with EtOAc and theorganic phase is dried over Na₂SO₄. After the desiccant and solvent havebeen eliminated the residue is purified on silica gel (EtOAc/MeOH/NH₃95:5:0.5).

Yield: 1.55 g (36% of theory). C₁₄H₁₇NO (M=215.298). Calc.: molpeak(M+H)⁺: 216 Found: molpeak (M+H)⁺: 216. R_(f) value: 0.48 (silica gel,EtOAc/MeOH/NH₃ 90:10:1).

2c 3-(4-pyrrolidin-1-ylmethyl-phenyl)-propan-1-ol

A solution of 1.65 g (7.66 mmol)3-(4-pyrrolidin-1-ylmethyl-phenyl)-prop-2-yn-1-ol in 20 mL EtOH iscombined with 200 mg 10% Pd/C and hydrogenated in the autoclave at RTand 30 psi H₂ until the theoretical uptake of hydrogen is achieved. Thecatalyst is suction filtered, the filtrate concentrated by evaporationand the residue is purified on silica gel (EtOAc/MeOH/NH₃ 90:10:1).

Yield: 0.81 g (48% of theory). C₁₄H₂₁NO (M=219.330). Calc.: molpeak(M+H)⁺: 220 Found: molpeak (M+H)⁺: 220. R_(f) value: 0.2 (silica gel,EtOAc/MeOH/NH₃ 90:10:1).

2d 3-(4-pyrrolidin-1-ylmethyl-phenyl)-propionaldehyde

2.87 mL (35.56 mmol) pyridine and 2.11 g (4.98 mmol) Dess-Martinperiodinane are added to a solution of 780 mg (3.56 mmol)3-(4-pyrrolidin-1-ylmethyl-phenyl)-propan-1-ol in 30 mL DCM. Thereaction mixture is stirred for 4 h at RT, then added to 100 mLsaturated, aqueous NaHCO₃ solution, exhaustively extracted withtert-butylmethylether, the organic phase is washed with saturated,aqueous NaCl solution and dried over Na₂SO₄. After the desiccant andsolvent have been eliminated the crude product is further reactedwithout purification.

Yield: 750 mg (97% of theory).

2e 1-(4-but-3-ynyl-benzyl)-pyrrolidine

815 mg (4.2 mmol) dimethyl (1-diazo-2-oxo-propyl)-phosphonate is addedto a mixture of 760 mg (3.5 mmol)3-(4-pyrrolidin-1-ylmethyl-phenyl)-propionaldehyde and 970 mg (7.0 mmol)K₂CO₃ in 100 mL dry MeOH under an argon atmosphere and stirred overnightat RT. The reaction mixture is diluted with diethyl ether, the organicphase is washed with saturated, aqueous NaHCO₃ solution and dried overNa₂SO₄. After the desiccant and solvent have been eliminated the residueis purified on silica gel (EtOAc/MeOH/NH₃ 95:5:0.5).

Yield: 200 mg (27% of theory). C₁₅H₁₉N (M=213.325). Calc.: molpeak(M+H)⁺: 214 Found: molpeak (M+H)⁺: 214. R_(f) value: 0.74 (silica gel,EtOAc/MeOH/NH₃ 95:5:0.5).

2f 5-bromo-2-[4-(4-pyrrolidin-1-ylmethyl-phenyl)-but-1-ynyl]-pyridine

A mixture of 200 mg (0.94 mmol) 1-(4-but-3-ynyl-benzyl)-pyrrolidine, 222mg (0.94 mmol) 2,5-dibromopyridine, 13.2 mg (0.02 mmol)tetrakis-triphenylphosphane-palladium, 3.6 mg (0.02 mmol) CuI and 0.27mL diisopropylamine in 10 mL THF is heated for 4 h at 40° C. under anargon atmosphere. The reaction mixture is diluted with water,exhaustively extracted with EtOAc, the organic phase is washed withsaturated, aqueous NaCl solution and dried over Na₂SO₄. After thedesiccant and solvent have been eliminated the residue is purified onsilica gel (EtOAc/MeOH/NH₃ 95:5:0.5).

Yield: 110 mg (32% of theory). C₂₀H₂₁BrN₂ (M=369.308). Calc.: molpeak(M+H)⁺: 369/371 Found: molpeak (M+H)⁺: 369/371. R_(f) value: 0.44(silica gel, EtOAc/MeOH/NH₃ 95:5:0.5).

2g5-(4-chloro-phenyl)-2-[4-(4-pyrrolidin-1-ylmethyl-phenyl)-but-1-ynyl]-pyridine

A mixture of 100 mg (0.27 mmol)5-bromo-2-[4-(4-pyrrolidin-1-ylmethyl-phenyl)-but-1-ynyl]-pyridine, 85mg (0.54 mmol) 4-chloro-phenylboric acid, 15.7 mg (0.014 mmol)tetrakis-triphenylphosphane-palladium, 0.28 mL of a 2 M aqueous Na₂CO₃solution in 10 mL 1,4-dioxane is heated for 8 h at 100° C. under anargon atmosphere. The solvent is distilled off i.vac., the residue istaken up in water, exhaustively extracted with EtOAc and dried overNa₂SO₄. After the desiccant and solvent have been eliminated the residueis purified over neutral Alox (ICN Alumina N+5% H₂O; cyc/EtOAc 7:3). Theproduct fractions are evaporated down, the residue is triturated with PEand suction filtered.

Yield: 12 mg (11% of theory). C₂₆H₂₅ClN₂ (M=400.956). Calc.: molpeak(M+H)⁺: 401/403 Found: molpeak (M+H)⁺: 401/403. R_(f) value: 0.41 (Alox,cyc/EtOAc 7:3).

EXAMPLE 2.15-(4-chloro-phenyl)-2-[4-(4-piperidin-1-ylmethyl-phenyl)-but-1-ynyl]-pyridine

2.1a 3-(4-hydroxymethyl-phenyl)-propionaldehyde

10.5 mL (152.8 mmol) allylalcohol, 18.8 g (62.2 mmol) Tetrabutylammoniumchloride monohydrate, 12.8 g (152.8 mmol) NaHCO₃ and 0.75 g (3.1 mmol)Pd(OAc)₂ is added to a solution of 15.0 g (62.2 mmol)4-iodobenzylalcohol in 100 mL DMF at RT under an N₂ atmosphere and thereaction solution is heated to 60° C. for 3 h. The solvent is eliminatedi.vac., the residue combined with 250 mL EtOAc and 80 mL water andsuction filtered through a fibreglass filter. 80 mL NaCl solution areadded to the filtrate, the phases are separated and the organic phase isdried over MgSO₄. After the desiccant and solvent have been eliminatedthe residue is purified by column chromatography on silica gel(gradient: cyc/EtOAc 3:1 after cyc/EtOAc 1:1).

Yield: 7.43 g (72.7% of theory). C₁₀H₁₂O₂ (M=164.206). Calc.: molpeak(M+H-H₂O)⁺: 147 Found: molpeak (M+H-H₂O)⁺: 147. HPLC retention time:5.26 min (method A).

2.1b (4-but-3-ynyl-phenyl)-methanol

8.5 g (61.5 mmol) K₂CO₃ are added to a solution of 5.0 g (30.4 mmol)3-(4-hydroxymethyl-phenyl)-propionaldehyde in 100 mL MeOH and then asolution of 7.0 g (36.4 mmol) dimethyl(1-diazo-2-oxo-propyl)-phosphonate in 50 mL MeOH is added dropwise andstirred for 3 h at RT. The reaction mixture is diluted with 200 mLEtOAc, washed with 80 mL saturated NaHCO₃ solution, the aqueous phaseextracted with 100 mL EtOAc and the combined organic phases are driedover Na₂SO₄. After the desiccant and solvent have been eliminated theresidue is purified by chromatography on silica gel (cyc/EtOAc 3:1).

Yield: 3.42 g (70.1% of theory). C₁₁H₁₂O (M=160.218). Calc.: molpeak(M+H-H₂O)⁺: 143 Found: molpeak (M+H)⁺: (M+H-H₂O)⁺: 143. R_(f) value:0.36 (silica gel, cyc/EtOAc 2:1).

2.1c(4-{4-[5-(4-chloro-phenyl)-pyridin-2-yl]-but-3-ynyl}-phenyl)-methanol

Under a nitrogen atmosphere 76 mg (0.4 mmol) CuI and 281 mg (0.4 mmol)Pd(PPh₃)₂Cl₂ are added to a solution of 1.27 g (7.92 mmol)(4-but-3-ynyl-phenyl)-methanol and 2.5 g (7.92 mmol)5-(4-chloro-phenyl)-2-iodo-pyridine in 40 mL triethylamine and 20 mL DMFand the reaction mixture is stirred for 2 h at 65° C. The solvent iseliminated in vacuo, the residue is dissolved in a little EtOAc and MeOHand purified by chromatography on silica gel (gradient: cyc/EtOAc 3:1 tocyc/EtOAc 1:1).

Yield: 1.48 g (53.6% of theory). C₂₂H₁₈ClNO (M=347.848). Calc.: molpeak(M+H)⁺: 348/350 Found: molpeak (M+H)⁺: 348/350. R_(f) value: 0.23(silica gel, cyc/EtOAc 2:1).

2.1d5-(4-chloro-phenyl)-2-[4-(4-piperidin-1-ylmethyl-phenyl)-but-1-ynyl]-pyridine

20 μL (0.26 mmol) methanesulphonic acid chloride and 45 μL (0.26 mmol)ethyldiisopropylamine are added to a solution, cooled to 0° C., of 75 mg(0.22 mmol)4-{4-[5-(4-chloro-phenyl)-pyridin-2-yl]-but-3-ynyl}-phenyl)-methanol in5 mL DCM and stirred at this temperature for 30 min. Then 108 μL (1.09mmol) piperidine are added and the reaction mixture is stirred for 72 hat RT. The reaction solution is evaporated down i.vac. and the residueis purified by HPLC.

Yield: 9.3 mg (53.6% of theory). C₂₇H₂₇ClN₂ (M=414.983). Calc.: molpeak(M+H)⁺: 415/417 Found: molpeak (M+H)⁺: 415/417. HPLC retention time:7.62 min (method A).

The following compounds are prepared as described in Example 2.1d:

HPLC retention time empirical mass in min Example R Yield (%) formulaspectrum (method) 2.2

19.3 C₂₅H₂₃ClN₂ 387/389[M + H]⁺ 7.04 (A) 2.3

24.4 C₃₁H₃₄ClN₃ 484/486[M + H]⁺ 5.96 (A) 2.4

13.1 C₂₅H₂₅ClN₂O 405/407[M + H]⁺ 6.95 (A) 2.5

22.4 C₂₉H₂₆ClN₃ 452/454[M + H]⁺ 7.71 (A) 2.6

11.4 C₂₇H₂₈ClN₃ 430/432[M + H]⁺ 6.87 (A) 2.7

25.9 C₃₁H₂₇ClN₂ 463/465[M + H]⁺ 8.26 (A) 2.8

24.7 C₂₇H₂₇ClN₂ 415/417[M + H]⁺ 7.53(A) 2.9

28.1 C₂₈H₂₄ClN₃ 438/440[M + H]⁺ 7.47 (A) 2.10

15.7 C₂₉H₃₂ClN₃ 458/460[M + H]⁺ 5.82 (A) 2.11

19.7 C₂₈H₂₉ClN₂O 445/447[M + H]⁺ 7.81 (A) 2.12

10.1 C₂₈H₂₉ClN₂O 445/447[M + H]⁺ 7.83 (A) 2.13

21.4 C₃₁H₃₄ClN₃O₂ 516/518[M + H]⁺ 8.18 (A) 2.14

25.1 C₂₈H₂₇ClN₂O₂ 459/461[M + H]⁺ 7.56 (A) 2.15

23.8 C₂₈H₂₉ClN₂ 429/431[M + H]⁺ 8.18 (A)

EXAMPLE 2.16 tert-butyl4-[(4-{4-[5-(4-chloro-phenyl)-pyridin-2-yl]-but-3-ynyl}-benzyl)-methyl-amino]-piperidin-1-carboxylate

Prepared analogously to Example 2.1d from 75 mg (0.22 mmol)4-{4-[5-(4-chlorophenyl)-pyridin-2-yl]-but-3-ynyl}-phenyl)-methanol and20 μL (1.09 mmol) 4 tert-butyl-methylamino-piperidin-1-carboxylate,stirring for 7 days at RT. To complete the reaction the reactionsequence described is repeated again using the same amount of reagentsand after 24 h reaction the mixture is worked up.

Yield: 8.5 mg (7.2% of theory). C₃₃H₃₈ClN₃O₂ (M=544.143). Calc.: molpeak(M+H)⁺: 544/546 Found: molpeak (M+H)⁺: 544/546. HPLC retention time:8.46 min (method A).

EXAMPLE 2.17(4-{4-[5-(4-chloro-phenyl)-pyridin-2-yl]-but-3-ynyl}-benzyl)-methyl-piperidin-4-yl-amine

0.5 mL trifluoroacetic acid are added to a solution of 35 mg (0.06 mmol)tert-butyl-4-[(4-{4-[5-(4-chloro-phenyl)-pyridin-2-yl]-but-3-ynyl}-benzyl)-methyl-amino]-piperidin-1-carboxylatein 3 mL DCM and the reaction mixture is stirred for 3 h at RT. Themixture is evaporated down i.vac., the residue is combined with 10 mLNaHCO₃ solution, extracted with 20 mL DCM and the organic phase is driedover Na₂SO₄. After the desiccant and solvent have been eliminated thedesired product is obtained.

Yield: 8.0 mg (28.2% of theory). C₂₈H₃₀ClN₃ (M=444.024). Calc.: molpeak(M+H)⁺: 444/446 Found: molpeak (M+H)⁺: 444/446. HPLC retention time:5.83 min (method A).

EXAMPLE 2.181-(4-{4-[5-(4-chloro-phenyl)-pyridin-2-yl]-but-3-ynyl}-benzyl)-pyrrolidin-3-ylamine

Prepared analogously to Example 2.17 from 17 mg (0.03 mmol) tert-butyl[1-(4-{4-[5-(4-chloro-phenyl)-pyridin-2-yl]-but-3-ynyl}-benzyl)-pyrrolidin-3-yl]-carbaminate(Example 2.13).

Yield: 12.0 mg (87.4% of theory). C₂₆H₂₆ClN₃ (M=415.970). Calc.: molpeak(M+H)⁺: 416/418 Found: molpeak (M+H)⁺: 416/418. HPLC retention time:5.83 min (method A).

EXAMPLE 2.191-(4-{4-[5-(4-chloro-phenyl)-pyridin-2-yl]-but-3-ynyl}-benzyl)-pyrrolidine-2-carboxylicacid

0.5 mL 1 M NaOH solution are added to a solution of 33 mg (0.07 mmol)methyl1-(4-{4-[5-(4-chloro-phenyl)-pyridin-2-yl]-but-3-ynyl}-benzyl)-pyrrolidine-2-carboxylate(Example 2.14) in 5 mL MeOH and the reaction mixture is stirred for 4 hat RT. The mixture is evaporated down i.vac., combined with 5 mL water,extracted with 10 mL EtOAc and the aqueous phase is saturated with NaCl,during which time the product is precipitated. It is evaporated downagain i.vac., the residue is combined with EtOH, filtered and thesolvent is eliminated.

Yield: 30.0 mg (93.6% of theory). C₂₇H₂₅ClN₂O₂ (M=444.966). Calc.:molpeak (M+H)⁺: 445/447 Found: molpeak (M+H)⁺: 445/447. HPLC retentiontime: 7.28 min (method A).

EXAMPLE 2.205-(2,4-dichloro-phenyl)-2-[4-(4-pyrrolidin-1-ylmethyl-phenyl)-but-1-ynyl]-pyridine

2.20a {4-[4-(5-bromo-pyridin-2-yl)-but-3-ynyl]-phenyl}-methanol

Under an N₂ atmosphere 130 mg (0.67 mmol) CuI and 300 mg (0.42 mmol)Pd(PPh₃)₂Cl₂ are added to a solution of 2.0 g (12.48 mmol)(4-but-3-ynyl-phenyl)-methanol and 3.2 g (13.1 mmol) 2,5-dibromopyridinein 80 mL triethylamine and the reaction mixture is stirred for 1.5 h at50° C. The solvent is eliminated in vacuo, the residue dissolved in alittle DCM and purified by chromatography on silica gel (gradient:cyc/EtOAc 4:1 to cyc/EtOAc 3:1).

Yield: 2.76 g (66.6% of theory). C₁₆H₁₄ BrNO (M=316.20). Calc.: molpeak(M+H)⁺: 316/318 Found: molpeak (M+H)⁺: 316/318. R_(f) value: 0.28(silica gel, cyc/EtOAc 2:1).

2.20b 5-bromo-2-[4-(4-pyrrolidin-1-ylmethyl-phenyl)-but-1-ynyl]-pyridine

0.24 mL (3.04 mmol) methanesulphonic acid chloride are added to asolution, cooled to 0° C., of 800 mg (2.53 mmol){4-[4-(5-bromo-pyridin-2-yl)-but-3-ynyl]-phenyl}-methanol in 17 mL DCMand then a solution of 0.52 mL ethyldiisopropylamine in 3 mL DCM isadded dropwise. The mixture is stirred for a further 30 min at 0° C.,0.51 mL (6.08 mmol) pyrrolidine is added, the reaction mixture is heatedto RT and kept at this temperature for 5 h. To complete the reactionanother 0.26 mL (3 mmol) pyrrolidine are added and stirred for 1 h atRT. The mixture is evaporated down i.vac., combined with 10 mL water and20 ml EtOAc, acidified with 1 M HCl and the organic phase is separatedoff. The aqueous phase is made alkaline with 2 M Na₂CO₃ solution,extracted with 20 mL EtOAc, the organic phase is separated off and driedover Na₂SO₄. After the desiccant and solvent have been eliminated thedesired product is obtained.

Yield: 630.0 mg (67.4% of theory). C₂₀H₂₁BrN₂ (M=369.308). Calc.:molpeak (M+H)⁺: 369/371 Found: molpeak (M+H)⁺: 369/371. HPLC retentiontime: 6.08 min (method A).

2.20c5-(2,4-dichloro-phenyl)-2-[4-(4-pyrrolidin-1-ylmethyl-phenyl)-but-1-ynyl]-pyridine

10 mg (0.01 mmol) tetrakis-triphenylphosphane-palladium are added to asuspension of 60 mg (0.16 mmol)5-bromo-2-[4-(4-pyrrolidin-1-ylmethyl-phenyl)-but-1-ynyl]-pyridine and63 mg (0.32 mmol) 2,4-dichlorophenylboric acid in 4 mL 1,4-dioxane and 1mL 2 M Na₂CO₃ solution and the reaction mixture is stirred for 1 h at110° C. The mixture is evaporated down i.vac. and the residue isextracted twice with in each case 15 mL EtOH. The solvent is removed andthe residue is purified by HPLC.

Yield: 22.7 mg (32.2% of theory). C₂₆H₂₄ Cl₂N₂ (M=435.401). Calc.:molpeak (M+H)⁺: 435/437/439 Found: molpeak (M+H)⁺: 435/437/439. HPLCretention time: 5.53 min (method C).

The following compounds are prepared as described in Example 2.20c:

HPLC retention time empirical mass in min Example R Yield (%) formulaspectrum (method) 2.21

13.0 C₂₆H₂₅BrN₂ 445/447[M + H]⁺ 5.53 (C) 2.22

41.4 C₂₇H₂₈N₂O 397[M + H]⁺ 3.39 (C) 2.23

30.8 C₂₆H₂₄Cl₂N₂ 435/437/439[M + H]⁺ 3.70 (A) 2.24

21.8 C₂₆H₂₄F₂N₂ 403[M + H]⁺ 7.21 (A) 2.25

7.5 C₂₈H₃₀N₂O 411[M + H]⁺ 7.30 (A)

EXAMPLE 2.265-(4-methoxy-phenyl)-2-[4-(4-pyrrolidin-1-ylmethyl-phenyl)-but-1-ynyl]-pyridine

Prepared analogously to Example 2.20c, after the reaction has ended thereaction mixture is combined with 10 mL water and 20 mL EtOAc, filteredthrough a fibreglass filter, the organic phase is separated off anddried over Na₂SO₄. The solvent is removed and the residue is purified byHPLC.

Yield: 17.4 mg (23.1% of theory). C₂₇H₂₈N₂O₂ (M=396.537). Calc.: molpeak(M+H)⁺: 397 Found: molpeak (M+H)⁺: 397. HPLC retention time: 8.15 min(method A).

EXAMPLE 2.274-(4-{4-[5-(4-chloro-phenyl)-pyridin-2-yl]-but-3-ynyl}-benzyl)-morpholine

2.27a 4-{4-[4-(5-bromo-pyridin-2-yl)-but-3-ynyl]-benzyl}-morpholine

36 μL (0.46 mmol) methanesulphonic acid chloride are added to asolution, cooled to 0° C., of 120 mg (0.38 mmol){4-[4-(5-bromo-pyridin-2-yl)-but-3-ynyl]-phenyl}-methanol (Example2.20a) in 5 mL DCM. A solution of 78 μL (0.46 mmol)ethyldiisopropylamine in 1 mL DCM is slowly added dropwise, the mixtureis stirred for a further 30 min at 0° C., then 80 μL (0.92 mmol) ofmorpholine are added, the mixture is allowed to come up to RT and keptat RT for 2 h. The mixture is evaporated down i.vac., the residue iscombined with 20 mL EtOAc and 10 mL water, acidified with 1 M HCl andthe phases are separated. The aqueous phase is combined with 2 M Na₂CO₃solution, extracted with 20 mL EtOAc and the organic phase is dried overNa₂SO₄. After the desiccant and solvent have been eliminated the productis obtained.

Yield: 146 mg (100% of theory). C₂₀H₂₁BrN₂O (M=385.307). Calc.: molpeak(M+H)⁺: 385/387 Found: molpeak (M+H)⁺: 385/387. HPLC retention time:5.92 min (method A).

2.27b4-(4-{4-[5-(4-chloro-phenyl)-pyridin-2-yl]-but-3-ynyl}-benzyl)-morpholine

Prepared analogously to Example 2.20c from 90 mg (0.23 mmol)4-{4-[4-(5-bromo-pyridin-2-yl)-but-3-ynyl]-benzyl}-morpholine and 73 mg(0.47 mmol) 4-chlorophenylboric acid.

Yield: 17.5 mg (17.9% of theory). C₂₆H₂₅ClN₂O (M=416.955). Calc.:molpeak (M+H)⁺: 417/419 Found: molpeak (M+H)⁺: 417/419. HPLC retentiontime: 7.51 min (method A).

EXAMPLE 2.28(4-{4-[5-(4-chloro-phenyl)-pyridin-2-yl]-but-3-ynyl}-benzyl)-cyclopropylmethyl-amine

2.28a(4-{4-[4-(5-bromo-pyridin-2-yl)-but-3-ynyl]-benzyl)-cyclopropylmethyl-amine

36 μL (0.46 mmol) methanesulphonic acid chloride are added to asolution, cooled to 0° C., of 120 mg (0.38 mmol){4-[4-(5-bromo-pyridin-2-yl)-but-3-ynyl]-phenyl}-methanol (Example2.20a) in 5 mL DCM. A solution of 78 μL (0.46 mmol)ethyldiisopropylamine in 1 mL DCM is slowly added dropwise, stirred fora further 30 min at 0° C., then 70 μL (0.92 mmol)C-cyclopropyl-methylamine are added, the reaction mixture is allowed tocome up to RT and kept at RT for 21 h. To complete the reaction another78 μL C-cyclopropyl-methylamine are added and stirred for another 5.5 hat RT. The reaction mixture is evaporated down i.vac. and the residuepurified by chromatography on silica gel (gradient: cyc/EtOAc 2:1 tocyc/EtOAc 1:1).

Yield: 70.0 mg (49.9% of theory). C₂₀H₂₁BrN₂ (M=369.308). Calc.: molpeak(M+H)⁺: 369/371 Found: molpeak (M+H)⁺: 369/371. HPLC retention time:6.55 min (method A).

2.28b(4-{4-[5-(4-chloro-phenyl)-pyridin-2-yl]-but-3-ynyl}-benzyl)-cyclopropylmethyl-amine

Prepared analogously to Example 2.20c from 65 mg (0.18 mmol)(4-{4-[4-(5-bromo-pyridin-2-yl)-but-3-ynyl]-benzyl)-cyclopropylmethyl-amineand 55 mg (0.35 mmol)) 4-chloro-phenylboric acid.

Yield: 15.4 mg (21.8% of theory). C₂₆H₂₅ClN₂ (M=400.956). Calc.: molpeak(M+H)⁺: 401/403 Found: molpeak (M+H)⁺: 401/403. HPLC retention time:7.63 min (method A).

EXAMPLE 2.293-(4-chloro-phenyl)-6-[4-(4-pyrrolidin-1-ylmethyl-phenyl)-but-1-ynyl]-pyridazine

2.29a 3-chloro-6-(4-chloro-phenyl)-pyridazine

Under an argon atmosphere a solution of 1.08 g (7.05 mmol)3,6-dichloro-pyridazin, 10 mL 2 M Na₂CO₃ solution and 80 mg (0.14 mmol)chlorine(di-2-norbornylphosphino)(2′-dimethylamino-1-1′-biphenyl-2-yl)palladium(II)in 150 mL 1,4-dioxane is heated to 110° C. At this temperature asolution of 1.13 g (7.05 mmol) 4-chlorophenyl-boric acid in 50 mL1,4-dioxane is added dropwise within 2 h and the reaction mixture isheated for another hour. After cooling it is combined with 100 mL water,extracted with 100 mL EtOAc and the organic phase is dried over Na₂SO₄.After the desiccant and solvent have been eliminated the residue ispurified by chromatography (silica gel, cyc/EtOAc 8:2).

Yield: 567 mg (35.7% of theory). C₁₀H₆Cl₂N₂ (M=225.079). Calc.: molpeak(M+H)⁺: 225/227 Found: molpeak (M+H)⁺: 225/227. R_(f) value: 0.29(silica gel, cyc/EtOAc 8:2).

2.29b3-(4-chloro-phenyl)-6-[4-(4-pyrrolidin-1-ylmethyl-phenyl)-but-1-ynyl]-pyridazin

Under an argon atmosphere 0.1 mL (0.72 mmol) triethylamine, 3 mg (0.02mmol) CuI and 8 mg (0.01 mmol)bis-triphenylphosphane-palladium(II)-chloride are added to a solution of77 mg (0.34 mmol) 3-chloro-6-(4-chloro-phenyl)-pyridazine and 73 mg(0.34 mmol) 1-(4-but-3-ynyl-benzyl)-pyrrolidine (Example 2e) in 4 mL DMFand the reaction mixture is stirred for 20 min at 100° C. and at 300 Win the microwave. The reaction mixture is combined with 10 mL water,extracted with 10 mL EtOAc and the organic phase is washed with waterand dried over Na₂SO₄. After the desiccant and solvent have beeneliminated the residue is purified by chromatography (silica gel,EtOAc/MeOH/NH₃ 90:10:1).

Yield: 6 mg (4.4% of theory). C₂₅H₂₄BrN₃ (M=401.943). Calc.: molpeak(M+H)⁺: 402/404 Found: molpeak (M+H)⁺: 402/404. R_(f) value: 0.66(silica gel, EtOAc/MeOH/NH₃ 90:10:1).

EXAMPLE 2.305-(4-chloro-phenyl)-2-[4-(4-pyrrolidin-1-ylmethyl-phenyl)-but-1-ynyl]-nicotinonitrile

Under an argon atmosphere 1.9 mg (0.1 mmol) CuI and 7 mg (0.1 mmol)Pd(PPh₃)₂Cl₂ are added to a solution of 50 mg (0.2 mmol)2-chloro-5-(4-chloro-phenyl)-nicotinonitrile and 43 mg (0.2 mmol)1-(4-but-3-ynyl-benzyl)-pyrrolidine in 2 mL DMF and 5 mL (20 mmol)triethylamine and the reaction mixture is stirred for 18 h at 50° C. Themixture is evaporated down i.vac., the residue is taken up in water,extracted exhaustively with EtOAc and the organic phase is dried overNa₂SO₄. After the desiccant and solvent have been eliminated the residueis is purified by HPLC.

Yield: 6.5 mg (7.6% of theory). C₂₇H₂₄BrN₃ (M=425.965). Calc.: molpeak(M+H)⁺: 425 Found: molpeak (M+H)⁺: 425. HPLC retention time: 6.80 min(method A).

EXAMPLE 3.15-(4-chloro-phenyl)-2-[3-chloro-4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridine

3.1a 5-(4-chloro-phenyl)-pyridin-2-ylamine

300 mL (600 mmol) of a 2 M Na₂CO₃ solution and 3.45 g (3.0 mmol)tetrakis-triphenylphosphane-palladium are added successively to asolution of 53.5 g (300 mmol) 2-amino-5-bromopyridine and 50.0 g (313mmol) 4-chlorophenylboric acid in 1.0 L 1,4-dioxane and 250 mL methanolunder argon. The reaction mixture is stirred for 2.5 h at 110° C. Thesolvent is eliminated i.vac., the residue is taken up in EtOAc andwater. The organic phase is dried over Na₂SO₄ and the solvent iseliminated i.vac. Further purification is carried out by columnchromatography on silica gel (gradient: DCM to DCM/MeOH 20:1).

Yield: 47 g (76.5% of theory). C₁₁H₉ClN₂ (M=204.661). Calc.: molpeak(M+H)⁺: 205/207 Found: molpeak (M+H)⁺: 205/207. HPLC retention time:5.15 min (method A).

3.1b 5-(4-chloro-phenyl)-2-iodo-pyridine

40.5 mL (33 mmol) tert-butylnitrite and 54 g (210 mmol) iodine are addedto a solution of 38 g (190 mmol) 5-(4-chloro-phenyl)-pyridin-2-ylaminein 400 mL carbon tetrachloride in a flask protected from light and themixture is stirred for 72 h at RT. A further 40.5 mL (33 mmol)tert-butylnitrite, 54 g (210 mmol) iodine and 100 mL DCM are added. Thereaction solution is stirred for a further 24 h at RT. The solvent iseliminated i.vac. and the residue taken up in 125 mL EtOAc and 50 mLwater. The aqueous phase is extracted once with EtOAc. The organic phaseis dried over Na₂SO₄ and stirred for one night over activated charcoal.After filtration the solvent is eliminated i.vac. Further purificationis carried out by column chromatography on silica gel (PE/EtOAc 9:1).

Yield: 35 g (58.4% of theory). C₁₁H₇ClIN (M=315.543). Calc.: molpeak(M+H)⁺: 316/318 Found: molpeak (M+H)⁺: 316/318. R_(f) value: 0.87(silica gel, PE/EtOAc 6:4).

3.1c 5-(4-chloro-phenyl)-2-trimethylsilanylethynyl-pyridine

34.9 mL (250 mmol) triethylamine and 20.8 mL (150.0 mmol)ethynyl-trimethyl-silane are added successively to a solution of 34 g(110 mmol) 5-(4-chloro-phenyl)-2-iodo-pyridine in 300 mL acetonitrileand 150 mL THF under an argon atmosphere. Then 803 mg (1.10 mmol)Pd(dppf)Cl₂ and 209 mg (1.10 mmol) CuI are added. The reaction solutionis stirred overnight at RT. The solvent is eliminated i.vac. and furtherpurification is carried out by column chromatography on silica gel(PE/EtOAc 8:2).

Yield: 15.3 g (48.7% of theory). C₁₆H₁₆ClNSi (M=285.852). Calc.: molpeak(M+H)⁺: 286/288 Found: molpeak (M+H)⁺: 286/288. HPLC retention time:7.10 min (method A).

3.1d 5-(4-chloro-phenyl)-2-ethynyl-pyridine

Under an argon atmosphere 6.6 g (21.0 mmol) TBAF are added to a solutionof 5.8 g (20.3 mmol)5-(4-chloro-phenyl)-2-trimethylsilanylethynyl-pyridine in 200 mL DCM at0° C. The reaction solution is stirred for 3 h, while the reactiontemperature slowly rises to RT. It is added to 50 mL water and theorganic phase is extracted four times with 50 mL water, dried over MgSO₄and filtered over activated charcoal. The solvent is eliminated i.vac.and further purification is carried out by column chromatography onsilica gel (PE/EtOAc 1:1).

Yield: 3.9 g (90.0% of theory). C₁₃H₈ClN (M=213.668). Calc.: molpeak(M+H)⁺: 214/216 Found: molpeak (M+H)⁺: 214/216. R_(f) value: 0.87(silica gel, cyc/EtOAc 8:2).

3.1e 1-[2-(4-bromo-2-chloro-phenoxy)-ethyl]-pyrrolidine

415 mg (3.00 mmol) K₂CO₃ and 170 mg (1.00 mmol)N-(2-chloroethyl)-pyrrolidine-hydrochloride is added to a solution of207 mg (1.00 mmol) 4-bromo-2-chloro-phenol in 5 mL DMF and the mixtureis stirred for 24 h at RT. The reaction mixture is diluted with 50 mLEtOAc, extracted once with 30 mL water and twice with 30 mLsemisaturated NaHCO₃ solution. The organic phase is dried over MgSO₄ andthe solvent is eliminated i.vac. Further purification is carried out bycolumn chromatography on silica gel (gradient: DCM to DCM/MeOH 9:1).

Yield: 100 mg (32.8% of theory). C₁₂H₁₅BrClNO (M=304.616). Calc.:molpeak (M+H)⁺: 304/306/308 Found: molpeak (M+H)⁺: 304/306/308. HPLCretention time: 5.59 min (method A).

3.1f5-(4-chloro-phenyl)-2-[3-chloro-4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridine

Under an argon atmosphere 0.14 mL (1.00 mmol) triethylamine, 11 mg (0.02mmol) Pd(PPh₃)₂Cl₂ and 2.9 mg (0.015 mmol) CuI are added successively toa solution of 71 mg (0.33 mmol) 5-(4-chloro-phenyl)-2-ethynyl-pyridineand 100 mg (0.33 mmol)1-[2-(4-bromo-2-chloro-phenoxy)-ethyl]-pyrrolidine in 3.0 mL DMF. Themixture is stirred for 10 min at 100° C. and at 200 Watt in themicrowave. The reaction solution is diluted with 30 mL EtOAc, washedtwice with semisaturated NaCl solution and the organic phase is driedover MgSO₄. The solvent is eliminated i.vac. and further purification iscarried out by column chromatography with HPLC-MS.

Yield: 12 mg (8.3% of theory). C₂₅H₂₂Cl₂N₂O (M=437.373). Calc.: molpeak(M+H)⁺: 437/439/441 Found: molpeak (M+H)⁺: 437/439/441. R_(f) value:0.28 (silica gel, DCM/MeOH 9:1).

EXAMPLE 3.25-(4-chloro-phenyl)-2-[3,5-dimethyl-4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridine

3.2a 1-[2-(4-bromo-2,6-dimethyl-phenoxy)-ethyl]-pyrrolidine

The product is obtained analogously to Example 3.1e from 201 mg (1.00mmol) 4-bromo-2,6-dimethyl-phenol and 170 mg (1.00 mmol)N-(2-chloroethyl)-pyrrolidine-hydrochloride.

Yield: 200 mg (67.1% of theory). C₁₄H₂₀BrNO (M=298.226). Calc.: molpeak(M+H)⁺: 298/300 Found: molpeak (M+H)⁺: 298/300. HPLC retention time:5.76 min (method A).

3.2b5-(4-chloro-phenyl)-2-[3,5-dimethyl-4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridine

The product is obtained analogously to Example 3.1f from 200 mg (0.67mmol) 1-[2-(4-bromo-2,6-dimethyl-phenoxy)-ethyl]-pyrrolidine and 143 mg(0.67 mmol) 5-(4-chloro-phenyl)-2-ethynyl-pyridine.

Yield: 5 mg (1.7% of theory). C₂₇H₂₇ClN₂O (M=430.982). Calc.: molpeak(M+H)⁺: 431/433 Found: molpeak (M+H)⁺: 431/433. R_(f) value: 0.29(silica gel, DCM/MeOH 9:1).

EXAMPLE 3.35-(4-chloro-phenyl)-2-[3-fluoro-4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridine

3.3a 1-[2-(4-bromo-2-fluoro-phenoxy)-ethyl]-pyrrolidine

The product is obtained analogously to Example 3.1e (acetonitrileinstead of DMF) from 0.57 mL (5.24 mmol) 4-bromo-2-fluoro-phenol and1.02 g (6.00 mmol) N-(2-chloroethyl)-pyrrolidine-hydrochloride.

Yield: 1.16 g (76.6% of theory). C₁₂H₁₅BrFNO (M=288.162). Calc.: molpeak(M+H)⁺: 288/290 Found: molpeak (M+H)⁺: 288/290. R_(f) value: 0.21(silica gel, EtOAc/MeOH 9:1).

3.3b 1-[2-(2-fluoro-4-iodo-phenoxy)-ethyl]-pyrrolidine

Prepared according to general working method 11 from1-[2-(4-bromo-2-fluoro-phenoxy)-ethyl]-pyrrolidine (1.10 g, 3.82 mmol).

Yield: 1.13 g (88.3% of theory). C₁₂H₁₅FINO (M=335.162). Calc.: molpeak(M+H)⁺: 336 Found: molpeak (M+H)⁺: 336. HPLC retention time: 4.79 min(method A).

3.3c5-(4-chloro-phenyl)-2-[3-fluoro-4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridine

Prepared according to general working method I from1-[2-(2-fluoro-4-iodo-phenoxy)-ethyl]-pyrrolidine (300 mg, 0.90 mmol)and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (201 mg, 0.94 mmol).

Yield: 150 mg (39.8% of theory). C₂₅H₂₂ClFIN₂O (M=420.918). Calc.:molpeak (M+H)⁺: 421/423 Found: molpeak (M+H)⁺: 421/423. HPLC retentiontime: 7.18 min (method A).

EXAMPLE 3.4 methyl5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-(2-pyrrolidin-1-yl-ethoxy)-benzoate

3.4a methyl 5-iodo-2-(2-pyrrolidin-1-yl-ethoxy)-benzoate

The product is obtained analogously to Example 3.1.e (acetonitrileinstead of DMF) from 10.0 g (36.0 mmol) methyl 5-iodo-salicylate and6.12 g (36.0 mmol) N-(2-chloroethyl)-pyrrolidine-hydrochloride.

Yield: 12.0 g (88.8% of theory). C₁₄H₁₈INO₃ (M=375.209). Calc.: molpeak(M+H)⁺: 376 Found: molpeak (M+H)⁺: 376. R_(f) value: 0.40 (silica gel,DCM/MeOH/NH₃ 9:1:0.1).

3.4b methyl5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-(2-pyrrolidin-1-yl-ethoxy)-benzoate

Prepared according to general working method I from methyl5-iodo-2-(2-pyrrolidin-1-yl-ethoxy)-benzoate (3.0 g, 8.0 mmol) and5-(4-chloro-phenyl)-2-ethynyl-pyridine (1.76 g, 8.24 mmol).

Yield: 1.02 g (26.9% of theory). C₂₇H₂₅ClN₂O₃ (M=460.965). Calc.:molpeak (M+H)⁺: 461/463 Found: molpeak (M+H)⁺: 461/463. HPLC retentiontime: 7.49 min (method A).

EXAMPLE 3.55-(4-chloro-phenyl)-2-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridine

3.5a 1-[2-(4-bromo-2-methoxy-phenoxy)-ethyl]-pyrrolidine

The product is obtained analogously to Example 3.1e (acetonitrileinstead of DMF) from 6.0 g (29.6 mmol) 4-bromo-2-methoxy-phenol and 5.63g (33.1 mmol) N-(2-chloroethyl)-pyrrolidine-hydrochloride.

Yield: 3.96 g (44.6% of theory). C₁₃H₁₈BrNO₂ (M=300.198). Calc.: molpeak(M+H)⁺: 300/302 Found: molpeak (M+H)⁺: 300/302. HPLC retention time:4.67 min (method A).

3.5b 1-[2-(4-iodo-2-methoxy-phenoxy)-ethyl]-pyrrolidine

Prepared according to general working method 11 from1-[2-(4-bromo-2-methoxy-phenoxy)-ethyl]-pyrrolidine (3.90 g, 13.0 mmol).

Yield: 4.19 g (92.9% of theory). C₁₃H₁₈INO₂ (M=347.198). Calc.: molpeak(M+H)⁺: 348 Found: molpeak (M+H)⁺: 348. HPLC retention time: 4.65 min(method A).

3.5c5-(4-chloro-phenyl)-2-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridine

Prepared according to general working method I from1-[2-(4-iodo-2-methoxy-phenoxy)-ethyl]-pyrrolidine (300 mg, 0.86 mmol)and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (194 mg, 0.91 mmol).

Yield: 106 mg (28.3% of theory). C₂₆H₂₅ClN₂O₂ (M=432.954). Calc.:molpeak (M+H)⁺: 433/435 Found: molpeak (M+H)⁺: 433/435. HPLC retentiontime: 7.44 min (method A).

EXAMPLE 3.65-(4-chloro-phenyl)-2-[4-(2-pyrrolidin-1-yl-ethoxy)-3-trifluoromethoxy-phenylethynyl]-pyridine

3.6a 4-bromo-2-trifluoromethoxy-phenol

1.55 mL (30.3 mmol) bromine in 50 mL DCM is added dropwise to a solutionof 5.0 g (28.1 mmol) 2-trifluoromethoxy-phenol in 70 mL DCM at −78° C.The reaction solution is heated to RT and stirred for a further 48 h.Then 70 mL Na₂SO₃ solution are added and the mixture is stirred untilthe orange colour has disappeared. The solution is diluted with DCM, theorganic phase is washed with NaCl solution, dried over MgSO₄ and thesolvent is eliminated i.vac. The purification is carried out by columnchromatography on silica gel (gradient: PE to PE:EtOAc 4:1).

Yield: 5.36 g (74.3% of theory). C₇H₄BrF₃O₂ (M=257.008). Calc.: molpeak(M−H)⁻: 255/257 Found: molpeak (M−H)⁻: 255/257. HPLC retention time:8.18 min (method A).

3.6b 1-[2-(4-bromo-2-trifluoromethoxy-phenoxy)-ethyl]-pyrrolidine

The product is obtained analogously to Example 3.1e (acetonitrileinstead of DMF) from 2.0 g (7.78 mmol) 4-bromo-2-trifluoromethoxy-phenoland 1.53 g (33.1 mmol) N-(2-chloroethyl)-pyrrolidine-hydrochloride.

Yield: 0.49 g (17.8% of theory). C₁₃H₁₅BrF₃NO₂ (M=354.169). Calc.:molpeak (M+H)⁺: 354/356 Found: molpeak (M+H)⁺: 354/356. HPLC retentiontime: 5.82 min (method A).

3.6c 1-[2-(4-iodo-2-trifluoromethoxy-phenoxy)-ethyl]-pyrrolidine

Prepared according to general working method 11 from1-[2-(4-bromo-2-trifluoromethoxy-phenoxy)-ethyl]-pyrrolidine (476 mg,1.34 mmol).

Yield: 540 mg (100.0% of theory). C₁₃H₁₅F₃INO₂ (M=401.170). Calc.:molpeak (M+H)⁺: 402 Found: molpeak (M+H)⁺: 402. HPLC retention time:6.07 min (method A).

3.6d5-(4-chloro-phenyl)-2-[4-(2-pyrrolidin-1-yl-ethoxy)-3-trifluoromethoxy-phenylethynyl]-pyridine

Prepared according to general working method I from1-[2-(4-iodo-2-trifluoromethoxy-phenoxy)-ethyl]-pyrrolidine (250 mg,0.62 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (140 mg, 0.65mmol).

Yield: 116 mg (38.5% of theory). C₂₆H₂₂ClF₃N₂O₂ (M=486.926). Calc.:molpeak (M+H)⁺: 487/489 Found: molpeak (M+H)⁺: 487/489. HPLC retentiontime: 8.09 min (method A).

EXAMPLE 3.72-[3-bromo-4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-5-(4-chloro-phenyl)-pyridine

3.7a 2-bromo-4-iodo-phenol

1.55 mL (30.3 mmol) bromine in 15 mL EtOAc is added dropwise to asolution of 4.0 g (18.2 mmol) 4-iodo-phenol in 35 mL EtOAc at RT. Thereaction solution is stirred for 2 h at RT. Then 75 mL Na₂SO₃ solutionis added and stirred until the orange colour has disappeared. Thesolution is diluted with DCM, the organic phase washed with NaClsolution, dried over MgSO₄ and the solvent is eliminated i.vac. A3.4:1.4:1.0 mixture of2-bromo-4-iodo-phenol:2,4-dibromo-phenol:4-bromo-phenol is obtained,which is further reacted without any more purification.

Yield of 2-bromo-4-iodo-phenol: 2.60 g (47.9% of theory). C₆H₄BrIO(M=298.907). Calc.: molpeak (M−H)⁻: 297/299 Found: molpeak (M−H)⁻:297/299. R_(f) value: 0.40 (silica gel, EtOAc/MeOH 9:1).

3.7b 1-[2-(2-bromo-4-iodo-phenoxy)-ethyl]-pyrrolidine

The product is obtained analogously to Example 3.1e from 1.0 g (1.15mmol, 59%) 2-bromo-4-iodo-phenol and 626 mg (3.68 mmol)N-(2-chloroethyl)-pyrrolidine-hydrochloride. A 4.7:1.0:1.0 mixture of1-[2-(2-bromo-4-iodo-phenoxy)-ethyl]-pyrrolidine:1-[2-(2,4-dibromo-phenoxy)-ethyl]-pyrrolidine:1-[2-(2-bromo-phenoxy)-ethyl]-pyrrolidineis obtained, which is further reacted without any more purification.

Yield 1-[2-(2-bromo-4-iodo-phenoxy)-ethyl]-pyrrolidine: 0.37 g (47.7% oftheory). C₁₂H₁₅BrINO (M=396.068). Calc.: molpeak (M+H)⁺: 397/399 Found:molpeak (M+H)⁺: 397/399. R_(f) value: 0.25 (silica gel, EtOAc/MeOH 9:1).

3.7c2-[3-bromo-4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-5-(4-chloro-phenyl)-pyridine

Prepared according to general working method I from1-[2-(2-bromo-4-iodo-phenoxy)-ethyl]-pyrrolidine (278 mg, 0.34 mmol,70%) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (110 mg, 0.52 mmol).

Yield: 152 mg (64.3% of theory). C₂₅H₂₂BrClN₂O (M=481.824). Calc.:molpeak (M+H)⁺: 481/483/485 Found: molpeak (M+H)⁺: 481/483/485. R_(f)value: 0.25 (silica gel, DCM/MeOH/NH₃ 9:1:0.1).

EXAMPLE 3.85-(4-chloro-phenyl)-2-[4-(2-pyrrolidin-1-yl-ethoxy)-3-trifluoromethyl-phenylethynyl]-pyridine

3.8a 4-bromo-2-trifluoromethyl-phenol

A solution of 3.0 g (11.8 mmol)4-bromo-1-methoxy-2-trifluoromethyl-benzene in 20 mL 1 M HBr in glacialacetic acid is stirred for 60 h at 90° C. The reaction solution isdiluted with 300 mL water, adjusted to pH 7 with K₂CO₃. The aqueousphase is extracted with EtOAc, the combined organic extracts are withwashed 40 mL quarter-saturated NaHCO₃ solution and dried over MgSO₄. Thesolvent is eliminated i.vac. and the product is further reacted withoutany more purification.

Yield: 1.20 g (42.3% of theory). C₇H₄BrF₃O (M=241.009). Calc.: molpeak(M−H)⁻: 239/241 Found: molpeak (M−H)⁻: 239/241. HPLC retention time:8.37 min (method A).

3.8b 1-[2-(4-bromo-2-trifluoromethyl-phenoxy)-ethyl]-pyrrolidine

The product is obtained analogously to Example 3.1e from 1.20 g (4.98mmol) 4-bromo-2-trifluoromethyl-phenol and 850 mg (5.00 mmol)N-(2-chloroethyl)-pyrrolidine-hydrochloride.

Yield: 400 mg (23.8% of theory). C₁₃H₁₅BrF₃NO (M=338.170). Calc.:molpeak (M+H)⁺: 338/340 Found: molpeak (M+H)⁺: 338/340. HPLC retentiontime: 5.91 min (method A).

3.8c 1-[2-(4-iodo-2-trifluoromethyl-phenoxy)-ethyl]-pyrrolidine

Prepared according to general working method II from1-[2-(4-bromo-2-trifluoromethyl-phenoxy)-ethyl]-pyrrolidine (400 mg,1.18 mmol).

Yield: 350 mg (76.8% of theory). C₁₃H₁₅F₃INO (M=385.170). Calc.: molpeak(M+H)⁺: 386 Found: molpeak (M+H)⁺: 386. HPLC retention time: 6.01 min(method A).

3.8d5-(4-chloro-phenyl)-2-[4-(2-pyrrolidin-1-yl-ethoxy)-3-trifluoromethyl-phenylethynyl]-pyridine

Prepared according to general working method I from1-[2-(4-iodo-2-trifluoromethyl-phenoxy)-ethyl]-pyrrolidine (180 mg, 0.47mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (83 mg, 0.39 mmol).

Yield: 35 mg (19.1% of theory). C₂₆H₂₂ClF₃N₂O (M=470.926). Calc.:molpeak (M+H)⁺: 471/473 Found: molpeak (M+H)⁺: 471/473. HPLC retentiontime: 8.23 min (method A).

EXAMPLE 3.95-(4-chloro-phenyl)-2-[2-methyl-4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridine

3.9a 1-[2-(4-bromo-3-methyl-phenoxy)-ethyl]-pyrrolidine

The product is obtained analogously to Example 3.1e (acetonitrileinstead of DMF) from 1.0 g (5.35 mmol) 4-bromo-3-methyl-phenol and 909mg (5.35 mmol) N-(2-chloroethyl)-pyrrolidine-hydrochloride.

Yield: 1.20 g (79.0% of theory). C₁₃H₁₈BrNO (M=284.199). Calc.: molpeak(M+H)⁺: 284/286 Found: molpeak (M+H)⁺: 284/286. HPLC retention time:3.64 min (method B).

3.9b5-(4-chloro-phenyl)-2-[2-methyl-4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridine

0.13 mL (1.00 mmol) triethylamine, 22 mg (0.02 mmol)tetrakis-triphenylphosphane-palladium and 3.7 mg (0.02 mmol) CuI areadded successively to a solution of 80 mg (0.37 mmol)5-(4-chloro-phenyl)-2-ethynyl-pyridine and 106 mg (0.37 mmol)1-[2-(4-bromo-3-methyl-phenoxy)-ethyl]-pyrrolidine in 3.0 mL DMF in anargon atmosphere. The mixture is stirred for 15 min at 100° C. and at200 Watt in the microwave. The reaction solution is diluted with 30 mLEtOAc, washed with semisaturated NaHCO₃ solution and the organic phaseis dried over MgSO₄. The solvent is eliminated i.vac. and the residue istriturated with tert-butylmethylether. The solvent is eliminated i.vac.and further purified by HPLC-MS.

Yield: 5.0 mg (3.2% of theory). C₂₆H₂₅ClN₂O (M=416.955). Calc.: molpeak(M+H)⁺: 417/419 Found: molpeak (M+H)⁺: 417/419. R_(f) value: 0.38(silica gel, DCM/MeOH/NH₃ 9:1:0.1).

EXAMPLE 3.105-(4-chloro-phenyl)-2-[2-chloro-4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridine

3.10a 1-[2-(4-bromo-3-chloro-phenoxy)-ethyl]-pyrrolidine

The product is obtained analogously to Example 3.1e (acetonitrileinstead of DMF) from 820 mg (4.82 mmol) 4-bromo-3-chloro-phenol and 1.0g (4.82 mmol) N-(2-chloroethyl)-pyrrolidine-hydrochloride.

Yield: 1.20 g (81.7% of theory). C₁₂H₁₅BrClNO (M=304.616). Calc.:molpeak (M+H)⁺: 304/306/308 Found: molpeak (M+H)⁺: 304/306/308. HPLCretention time: 3.69 min (method B).

3.10b5-(4-chloro-phenyl)-2-[2-chloro-4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridine

Under an argon atmosphere 0.13 mL (1.00 mmol) triethylamine, 22 mg (0.02mmol) tetrakis-triphenylphosphane-palladium and 3.7 mg (0.02 mmol) CuIare added successively to a solution of 80 mg (0.37 mmol)5-(4-chloro-phenyl)-2-ethynyl-pyridine and 114 mg (0.37 mmol)1-[2-(4-bromo-3-chloro-phenoxy)-ethyl]-pyrrolidine in 3.0 mL DMF. Themixture is stirred for 15 min at 100° C. and at 200 W in the microwave.The reaction solution is diluted with 40 mL EtOAc, washed twice withsemisaturated NaHCO₃ solution and the organic phase is dried over MgSO₄.The solvent is eliminated i.vac. and the residue is triturated withtert-butylmethylether. The solvent is eliminated i.vac. and furtherpurification is carried out by column chromatography with HPLC-MS.

Yield: 12.0 mg (7.3% of theory). C₂₅H₂₂Cl₂N₂O (M=437.373). Calc.:molpeak (M+H)⁺: 437/439/441 Found: molpeak (M+H)⁺: 437/439/441. HPLCretention time: 4.91 min (method B).

EXAMPLE 3.115-(4-chloro-phenyl)-2-[3-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridine

3.11a 1-[2-(3-iodo-phenoxy)-ethyl]-pyrrolidine

The product is obtained analogously to Example 3.1e (acetonitrileinstead of DMF) from 1.06 g (4.82 mmol) 3-iodo-phenol and 820 mg (4.82mmol) N-(2-chloroethyl)-pyrrolidine-hydrochloride.

Yield: 1.20 g (78.5% of theory). C₁₂H₁₆INO (M=317.172). Calc.: molpeak(M+H)⁺: 318 Found: molpeak (M+H)⁺: 318. HPLC retention time: 5.01 min(method A).

3.11b5-(4-chloro-phenyl)-2-[3-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridine

Prepared according to general working method I from1-[2-(3-iodo-phenoxy)-ethyl]-pyrrolidine (119 mg, 0.37 mmol) and5-(4-chloro-phenyl)-2-ethynyl-pyridine (80 mg, 0.37 mmol).

Yield: 14 mg (9.3% of theory). C₂₅H₂₃ClN₂O (M=402.928). Calc.: molpeak(M+H)⁺: 403/405 Found: molpeak (M+H)⁺: 403/405. HPLC retention time:4.07 min (method A).

EXAMPLE 3.125-(4-chloro-phenyl)-2-[3-(3-pyrrolidin-1-yl-propoxy)-phenylethynyl]-pyridine

3.12a 1-[3-(3-iodo-phenoxy)-propyl]-pyrrolidine

The product is obtained analogously to Example 3.1e (acetonitrileinstead of DMF) from 2.7 g (12.2 mmol) 3-iodo-phenol and 1.80 mg (12.2mmol) N-(3-chloropropyl)-pyrrolidine.

Yield: 3.60 g (89.2% of theory). C₁₃H₁₈INO (M=331.199). Calc.: molpeak(M+H)⁺: 332 Found: molpeak (M+H)⁺: 332. HPLC retention time: 5.42 min(method A).

3.12b5-(4-chloro-phenyl)-2-[3-(3-pyrrolidin-1-yl-propoxy)-phenylethynyl]-pyridine

Prepared according to general working method I from1-[3-(3-iodo-phenoxy)-propyl]-pyrrolidine (124 mg, 0.37 mmol) and5-(4-chloro-phenyl)-2-ethynyl-pyridine (80 mg, 0.37 mmol).

Yield: 54 mg (34.6% of theory). C₂₆H₂₅ClN₂O (M=416.955). Calc.: molpeak(M+H)⁺: 416/418 Found: molpeak (M+H)⁺: 416/418. HPLC retention time:4.99 min (method B).

EXAMPLE 3.135-(4-chloro-phenyl)-2-[3-nitro-4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridine

3.13a 1-[2-(4-bromo-2-nitro-phenoxy)-ethyl]-pyrrolidine

The product is obtained analogously to Example 3.1e (acetonitrileinstead of DMF) from 10.5 g (48.2 mmol) 4-bromo-3-nitro-phenol and 8.2mg (48.2 mmol) N-(2-chloroethyl)-pyrrolidine-hydrochloride.

Yield: 1.0 g (6.6% of theory). C₁₂H₁₅BrN₂O₃ (M=315.17). Calc.: molpeak(M+H)⁺: 315/317 Found: molpeak (M+H)⁺: 315/317. R_(f) value: 0.30(silica gel, DCM/MeOH/NH₃ 9:1:0.1).

3.13b 1-[2-(4-iodo-2-nitro-phenoxy)-ethyl]-pyrrolidine

Prepared according to general working method II from1-[2-(4-bromo-2-nitro-phenoxy)-ethyl]-pyrrolidine (1.0 g, 2.22 mmol).

Yield: 600 mg (74.6% of theory). C₁₂H₁₅IN₂O₃ (M=362.17). Calc.: molpeak(M+H)⁺: 363 Found: molpeak (M+H)⁺: 363. R_(f) value: 0.35 (silica gel,DCM/MeOH/NH₃ 9:1:0.1).

3.13c5-(4-chloro-phenyl)-2-[3-nitro-4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridine

Prepared according to general working method I from1-[2-(4-iodo-2-nitro-phenoxy)-ethyl]-pyrrolidine (600 mg, 1.66 mmol) and5-(4-chloro-phenyl)-2-ethynyl-pyridine (363 mg, 1.70 mmol).

Yield: 100 mg (13.1% of theory). C₂₅H₂₂ClN₃ O₃ (M=447.93). Calc.:molpeak (M+H)⁺: 448/450 Found: molpeak (M+H)⁺: 448/450. R_(f) value:0.35 (silica gel, DCM/MeOH/NH₃ 9:1:0.1).

EXAMPLE 3.14 methyl5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-3-methyl-2-(2-pyrrolidin-1-yl-ethoxy)-benzoate

3.14a 2-hydroxy-5-iodo-3-methyl-benzoic acid

14.9 mL (24.1 mmol) sodium hypochlorite solution (10 percent by weightin water) is added dropwise to a solution of 4.0 g (24.1 mmol) methyl2-hydroxy-3-methyl-benzoate, 3.6 g (24.1 mmol) NaI, 0.96 g (24.1 mmol)NaOH in 100 mL MeOH at −5° C. over 40 min. The reaction is stirred for30 min at −5° C. and 5 days at RT. The solvent is eliminated i.vac. andthe residue is taken up in 80 mL water and 50 mL DCM. After the organicphase has been saturated with NaCl it is extracted twice with DCM. Thecombined organic extracts are filtered and the solvent is eliminatedi.vac. The product is further reacted without any more purification.

Yield: 7.25 g (108% of theory). C₈H₇IO₃ (M=278.048). Calc.: molpeak(M+H)⁺: 279 Found: molpeak (M+H)⁺: 279. HPLC retention time: 8.41 min(method A).

3.14b methyl 2-hydroxy-5-iodo-3-methyl-benzoate

A solution of 2.0 g (7.19 mmol) 2-hydroxy-5-iodo-3-methyl-benzoic acidin 5.0 mL thionyl chloride (69.0 mmol) is stirred for 20 min at 80° C.Thionyl chloride is eliminated i.vac. and the residue is combined with20 mL MeOH and stirred for 20 min at RT. The product is precipitated outof the reaction. MeOH is eliminated i.vac. down to 5 mL and the residueis suction filtered. The product is further reacted without any morepurification.

Yield: 1.14 g (54.3% of theory). C₉H₉IO₃ (M=292.075). Calc.: molpeak(M−H)⁻: 291 Found: molpeak (M−H)⁻: 291. R_(f) value: 0.96 (silica gel,EtOAc).

3.14c methyl 5-iodo-3-methyl-2-(2-pyrrolidin-1-yl-ethoxy)-benzoate

The product is obtained analogously to Example 3.1e from 1.1 g (3.77mmol) methyl 2-hydroxy-5-iodo-3-methyl-benzoate and 641 mg (3.77 mmol)N-(2-chloroethyl)-pyrrolidine-hydrochloride.

Yield: 347 mg (23.7% of theory). C₁₅H₂₀INO₃ (M=389.236). Calc.: molpeak(M+H)⁺: 390 Found: molpeak (M+H)⁺: 390. HPLC retention time: 6.20 min(method A).

3.14d methyl5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-3-methyl-2-(2-pyrrolidin-1-yl-ethoxy)-benzoate

Prepared according to general working method I from methyl5-iodo-3-methyl-2-(2-pyrrolidin-1-yl-ethoxy)-benzoate (150 mg, 0.39mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (112 mg, 0.53 mmol).

Yield: 31 mg (17.1% of theory). C₂₈H₂₇ClN₂O₃ (M=474.992). Calc.: molpeak(M+H)⁺: 475/477 Found: molpeak (M+H)⁺: 475/477. HPLC retention time:8.11 min (method A).

EXAMPLE 3.155-(4-chloro-phenyl)-2-[2-(2-pyrrolidin-1-yl-ethoxy)-pyridin-5-yl-ethynyl]-pyridine

3.15a 5-bromo-2-(2-pyrrolidin-1-yl-ethoxy)-pyridine

280 mg (7.00 mmol, 60%) NaH are added to a solution of 0.76 mL (6.14mmol) N-(2-hydroxyethyl)pyrrolidine in 20 mL DMF at RT. The reactionsolution is stirred for 45 min at RT and then 1.35 g (5,53 mmol)2,5-dibromopyridine are added. The solution is stirred for 16 h at 70°C. and the solvent is eliminated i.vac. The residue is taken up in 100mL EtOAc and 50 mL water and the organic phase is extracted with 40 mLsaturated NaCl solution. The organic phase is dried over Na₂SO₄ and thesolvent is eliminated i.vac. Further purification is carried out bycolumn chromatography on silica gel (gradient: cyc/EtOAc 1:1 to EtOAc).

Yield: 926 mg (61.8% of theory). C₁₁H₁₅BrN₂O (M=271.159). Calc.: molpeak(M+H)⁺: 271/273 Found: molpeak (M+H)⁺: 271/273. R_(f) value: 0.05(silica gel, cyc/EtOAc 2:1).

3.15b5-(4-chloro-phenyl)-2-[2-(2-pyrrolidin-1-yl-ethoxy)-pyridin-5-yl-ethynyl]-pyridine

Prepared according to general working method I from5-bromo-2-(2-pyrrolidin-1-yl-ethoxy)-pyridine (90 mg, 0.33 mmol) and5-(4-chloro-phenyl)-2-ethynyl-pyridine (80 mg, 0.37 mmol).

Yield: 19 mg (13.8% of theory). C₂₄H₂₂ClN₃O (M=403.915). Calc.: molpeak(M+H)⁺: 404/406 Found: molpeak (M+H)⁺: 404/406. R_(f) value: 0.38(silica gel, DCM/MeOH/NH₃ 9:1:0.1).

EXAMPLE 3.165-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-(2-pyrrolidin-1-yl-ethoxy)-pyrimidine

3.16a 5-bromo-2-(2-pyrrolidin-1-yl-ethoxy)-pyrimidine

50 mg (1.15 mmol, 60%) NaH are added to a solution of 0.17 mL (1.38mmol) N-(2-hydroxyethyl)pyrrolidine in 10 mL THF at RT. The reactionsolution is stirred for 15 min at RT and then 200 mg (1.03 mmol)5-bromo-2-chloropyrimidine are added. The solution is stirred for 16 hat RT. 10 mL water are added and the aqueous phase is extracted with 20mL EtOAc. The organic phase is dried over Na₂SO₄ and the solvent iseliminated i.vac. Further purification is carried out by columnchromatography on silica gel (DCM/MeOH/NH₃ 9:1:0.1).

Yield: 200 mg (71.1% of theory). C₁₀H₁₄BrN₃O (M=272.147). Calc.: molpeak(M+H)⁺: 272/274 Found: molpeak (M+H)⁺: 272/274. R_(f) value: 0.47(silica gel, DCM/MeOH/NH₃ 9:1:0.1).

3.16b5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-(2-pyrrolidin-1-yl-ethoxy)-pyrimidine

Under an argon atmosphere 0.11 mL (0.79 mmol) triethylamine, 7 mg (0.01mmol) tetrakis-triphenylphosphane-palladium and 1.3 mg (0.01 mmol) CuIare added successively to a solution of 56 mg (0.26 mmol)5-(4-chloro-phenyl)-2-ethynyl-pyridine and 71 mg (0.26 mmol)5-bromo-2-(2-pyrrolidin-1-yl-ethoxy)-pyrimidine in 3.0 mL DMF. Themixture is stirred for 20 min at 100° C. and at 300 Watt in themicrowave. The reaction solution is diluted with 10 mL water and theaqueous phase is extracted with 20 mL EtOAc. The organic phase isextracted with saturated NaCl solution and dried over Na₂SO₄. Thesolvent is eliminated i.vac. and further purification is carried out bycolumn chromatography with HPLC-MS.

Yield: 7 mg (6.6% of theory). C₂₃H₂₁ClN₄O (M=404.903). Calc.: molpeak(M+H)⁺: 405/407 Found: molpeak (M+H)⁺: 405/407. R_(f) value: 0.39(silica gel, DCM/MeOH/NH₃ 9:1:0.1).

EXAMPLE 3.173-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-6-(2-pyrrolidin-1-yl-ethoxy)-pyridazine

3.17a 3-chloro-6-(2-pyrrolidin-1-yl-ethoxy)-pyridazine

175 mg (4.01 mmol, 55%) NaH are added to a solution of 0.50 mL (4.04mmol) N-(2-hydroxyethyl)pyrrolidine in 50 mL THF at 0° C. The reactionsolution is stirred for 60 min and heated to RT. 500 mg (3.26 mmol)3,6-dichloro-pyridazine are added. The solution is stirred for 5 h atRT. 50 mL water are added and the aqueous phase is extracted with 100 mLEtOAc. The organic phase is extracted once with saturated NaCl solutionand dried over Na₂SO₄. The solvent is eliminated i.vac. and furtherpurification is carried out by column chromatography on silica gel(gradient: EtOAc to EtOAc/MeOH/NH₃ 9:1:0.1).

Yield: 652 mg (87.9% of theory). C₁₀H₁₄ClN₃O (M=227.696). Calc.: molpeak(M+H)⁺: 228/230 Found: molpeak (M+H)⁺: 228/230. R_(f) value: 0.45(silica gel, EtOAc/MeOH/NH₃ 9:1:0.1).

3.17b3-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-6-(2-pyrrolidin-1-yl-ethoxy)-pyridazine

Under an argon atmosphere 0.11 mL (0.79 mmol) triethylamine, 4 mg (0.01mmol)chlorine(di-2-norbornylphosphino)(2′-dimethylamino-1-1′-biphenyl-2-yl)palladium(II)and 1.2 mg (0.01 mmol) CuI are added successively to a solution of 57 mg(0.27 mmol) 5-(4-chloro-phenyl)-2-ethynyl-pyridine and 61 mg (0.26 mmol)3-chloro-6-(2-pyrrolidin-1-yl-ethoxy)-pyridazine in 3.0 mL DMF. Themixture is stirred for 20 min at 100° C. and 300 Watt in the microwave.The reaction solution is diluted with 10 mL water and the aqueous phaseis extracted with 20 mL EtOAc. The organic phase is extracted withsaturated NaCl solution and dried over Na₂SO₄. The solvent is eliminatedi.vac. and further purification is carried out by column chromatographywith HPLC-MS.

Yield: 3 mg (2.9% of theory). C₂₃H₂₁ClN₄O (M=404.903). Calc.: molpeak(M+H)⁺: 405/407 Found: molpeak (M+H)⁺: 405/407. HPLC retention time:6.39 min (method A).

EXAMPLE 3.185-(4-chloro-phenyl)-2-[4-(1-ethyl-piperidin-3-yloxy)-phenylethynyl]-pyridine

3.18a 3-(4-bromo-phenoxy)-1-ethyl-piperidine

652 mg (2.00 mmol) caesium carbonate, 36 mg (0.20 mmol)1,10-phenanthroline and 19 mg (0.10 mmol) CuI are added to a solution of289 mg (1.00 mmol) 1-bromo-4-iodobenzene and 0.27 mL (2.00 mmol)N-ethyl-3-hydroxypiperidine in 1.0 mL toluene. The reaction mixture isstirred for 36 h at 110° C. and then combined with 10 mL water and 10 mLEtOAc. After filtration the aqueous phase is extracted with 10 mL EtOAcand the combined organic extracts are washed with saturated NaClsolution and dried over Na₂SO₄. The solvent is eliminated i.vac. andfurther purification is carried out by column chromatography on silicagel (EtOAc).

Yield: 100 mg (35.2% of theory). C₁₃H₁₈BrNO (M=284.199). Calc.: molpeak(M+H)⁺: 284/286 Found: molpeak (M+H)⁺: 284/286. R_(f) value: 0.50(silica gel, EtOAc).

3.18b5-(4-chloro-phenyl)-2-[4-(1-ethyl-piperidin-3-yloxy)-phenylethynyl]-pyridine

Prepared according to general working method I from3-(4-bromo-phenoxy)-1-ethyl-piperidine (90 mg, 0.32 mmol) and5-(4-chloro-phenyl)-2-ethynyl-pyridine (68 mg, 0.32 mmol).

Yield: 24 mg (18.1% of theory). C₂₆H₂₅ClN₂O (M=416.955). Calc.: molpeak(M+H)⁺: 417/419 Found: molpeak (M+H)⁺: 417/419. R_(f) value: 0.69(silica gel, EtOAc/MeOH/NH₃ 9:1:0.1).

EXAMPLE 3.19(S)-3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-1-aza-bicyclo[2.2.2]octane

3.19a (S)-3-(4-bromo-phenoxy)-1-aza-bicyclo[2.2.2]octane

The product is obtained analogously to Example 3.18a from 577 mg (2.00mmol) 1-bromo-4-iodobenzene and 254 mg (2.00 mmol)(S)-(+)-3-hydroxyquinuclidine.

Yield: 170 mg (30.1% of theory). C₁₃H₁₆BrNO (M=282.183). Calc.: molpeak(M+H)⁺: 282/284 Found: molpeak (M+H)⁺: 282/284. R_(f) value: 0.28(silica gel, EtOAc/MeOH/NH₃ 9:1:0.1).

3.19b(S)-3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-1-aza-bicyclo[2.2.2]octane

Prepared according to general working method I from(S)-3-(4-bromo-phenoxy)-1-aza-bicyclo[2.2.2]octane (170 mg, 0.62 mmol)and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (100 mg, 0.47 mmol).

Yield: 3.4 mg (1.8% of theory). C₂₆H₂₃ClN₂O (M=414.939). Calc.: molpeak(M+H)⁺: 415/417 Found: molpeak (M+H)⁺: 415/417. R_(f) value: 0.11(silica gel, EtOAc/MeOH/NH₃ 9:1:0.1).

EXAMPLE 3.20(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-ethyl)-pyridin-4-yl-amine

3.20a tert-butylpyridin-4-yl-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-carbaminate

309 mg (7.72 mmol, 60%) NaH is added to a solution of 1.50 g (7.72 mmol)tert-butyl pyridin-4-yl-carbaminate in 80 mL DMF at 0° C. The reactionis stirred for 1 h and at the same time heated to RT. 2.09 g (10.00mmol) 2-(2-bromoethoxy)tetrahydro-2H-pyrane in 20 mL DMF is added within10 min. The reaction mixture is stirred for 16 h at RT and combined with50 mL water and 100 mL EtOAc. The organic phase is dried over Na₂SO₄ andthe solvent is eliminated i.vac. Further purification is carried out bycolumn chromatography on silica gel (cyc/EtOAc 7:3).

Yield: 1.08 g (43.4% of theory). C₁₇H₂₆BrN₂O₄ (M=322.408). R_(f) value:0.25 (silica gel, EtOAc/cyc 8:2).

3.20b 2-(pyridin-4-ylamino)-ethanol

Trifluoroacetic acid is added to a solution of 1.08 g (3.35 mmol)tert-butyl pyridin-4-yl-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-carbaminatein DCM at 0° C., heated to RT and stirred for 16 h. The reaction mixtureis cooled to 0° C. and made alkaline with saturated K₂CO₃ solution. Theaqueous phase is extracted with 50 mL EtOAc, the organic phase is driedover Na₂SO₄ and the solvent is eliminated i.vac. Further purification iscarried out by column chromatography on silica gel (EtOAc/MeOH/NH₃9:1:0.1).

Yield: 120 mg (25.9% of theory). C₇H₁₀N₂O (M=138.171). Calc.: molpeak(M+H)⁺: 139 Found: molpeak (M+H)⁺: 139. R_(f) value: 0.18 (silica gel,EtOAc/MeOH/NH₃ 9:1:0.1).

3.20c [2-(4-bromo-phenoxy)-ethyl]-pyridin-4-yl-amine

The product is obtained analogously to Example 3.18a from 251 mg (0.87mmol) 1-bromo-4-iodobenzene and 120 mg (0.86 mmol)2-(pyridin-4-ylamino)-ethanol.

Yield: 90 mg (35.4% of theory). C₁₃H₁₃BrN₂O (M=293.165). Calc.: molpeak(M+H)⁺: 293/295 Found: molpeak (M+H)⁺: 293/295. R_(f) value: 0.50(silica gel, EtOAc/MeOH/NH₃ 9:1:0.1).

3.20d [2-(4-iodo-phenoxy)-ethyl]-pyridin-4-yl-amine

Prepared according to general working method II from[2-(4-bromo-phenoxy)-ethyl]-pyridin-4-yl-amine (90 mg, 0.31 mmol).

Yield: 95 mg (91.0% of theory). C₁₃H₁₃IN₂O (M=340.166). HPLC retentiontime: 5.86 min (method A).

3.20e(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-ethyl)-pyridin-4-yl-amine

Prepared according to general working method I from[2-(4-iodo-phenoxy)-ethyl]-pyridin-4-yl-amine (95 mg, 0.28 mmol) and5-(4-chloro-phenyl)-2-ethynyl-pyridine (70 mg, 0.33 mmol).

Yield: 30 mg (25.2% of theory). C₂₆H₂₀ClN₃O (M=425.922). Calc.: molpeak(M+H)⁺: 426/428 Found: molpeak (M+H)⁺: 426/428. R_(f) value: 0.38(silica gel, EtOAc/MeOH/NH₃ 9:1:0.1).

EXAMPLE 3.215-(4-chloro-phenyl)-2-{4-[2-(2,2,6,6-tetramethyl-piperidin-1-yl)-ethoxy]-phenylethynyl}-pyridine

3.21a 1-[2-(4-iodo-phenoxy)-ethyl]-2,2,6,6-tetramethyl-piperidine

The product is obtained analogously to Example 3.1e from 500 mg (2.27mmol) 4-iodo-phenol and 500 mg (2.08 mmol)1-(2-chloro-ethyl)-2,2,6,6-tetramethyl-piperidine.

Yield: 673 mg (83.5% of theory). C₁₇H₂₆INO (M=387.307). Calc.: molpeak(M+H)⁺: 388 Found: molpeak (M+H)⁺: 388. R_(f) value: 0.79 (silica gel,cyc/EtOAc 4:1).

3.21b5-(4-chloro-phenyl)-2-{4-[2-(2,2,6,6-tetramethyl-piperidin-1-yl)-ethoxy]-phenylethynyl}-pyridine

Prepared according to general working method I from1-[2-(4-iodo-phenoxy)-ethyl]-2,2,6,6-tetramethyl-piperidine (260 mg,0.67 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (155 mg, 0.73mmol).

Yield: 31 mg (9.8% of theory). C₃₀H₃₃ClN₂O (M=473.063). Calc.: molpeak(M+H)⁺: 473/475 Found: molpeak (M+H)⁺: 473/475. R_(f) value: 0.21(silica gel, cyc/EtOAc 3:1).

EXAMPLE 3.225-(4-chloro-phenyl)-2-[4-(3-pyrrolidin-1-yl-propyl)-phenylethynyl]-pyridine

3.22a 3-(4-bromo-phenyl)-propionaldehyde

210 mg (0.86 mmol) Pd(OAc)₂, 5.23 g (17.32 mmol) tetra-n-butylammoniumchloride and 3.6 g NaHCO₃ are added to a solution of 5.0 g (17.32 mmol)4-bromo-iodo-benzene and 3.0 mL (43.67 mmol) allylalcohol in 30 mL DMF.The reaction solution is stirred for 2 h at 60° C. and diluted With 50mL water. The aqueous phase is extracted with 50 mL EtOAc and thecombined organic extracts are washed with 50 mL saturated NaCl solution.The organic phase is dried over Na₂SO₄ and the solvent is eliminatedi.vac. Further purification is carried out by column chromatography onsilica gel (cyc/EtOAc 3:1).

Yield: 2.48 g (67.2% of theory). C₉H₉BrO (M=213.075). Calc.: molpeak(M−H)⁻: 211/213 Found: molpeak (M−H)⁻: 211/213. R_(f) value: 0.43(silica gel, cyc/EtOAc 4:1).

3.22b 1-[3-(4-bromo-phenyl)-propyl]-pyrrolidine

A solution of 1.03 g (4.82 mmol) 3-(4-bromo-phenyl)-propionaldehyde and0.41 mL (4.82 mmol) pyrrolidine in 50 mL MeOH is adjusted to pH 4-5 withglacial acetic acid. Then 400 mg (6.05 mmol) NaBH₃CN are added batchwiseand the reaction is stirred for 3 days at RT. The reaction solution isdiluted with 30 mL water and the aqueous phase is extracted with 50 mLEtOAc. The organic phase is dried over Na₂SO₄ and the solvent iseliminated i.vac. Further purification is carried out by columnchromatography on silica gel (EtOAc/MeOH/NH₃ 9:1:0.1).

Yield: 1.06 g (82.1% of theory). C₁₃H₁₈BrN (M=268.199). Calc.: molpeak(M+H)⁺: 268/270 Found: molpeak (M+H)⁺: 268/270. R_(f) value: 0.50(silica gel, EtOAc/MeOH/NH₃ 9:1:0.1).

3.22c5-(4-chloro-phenyl)-2-[4-(3-pyrrolidin-1-yl-propyl)-phenylethynyl]-pyridine

The product is obtained analogously to Example 3.16b (Pd(PPh₃)₂Cl₂instead of tetrakis-triphenylphosphane-palladium) from 72 mg (0.27 mmol)1-[3-(4-bromo-phenyl)-propyl]-pyrrolidine and 57 mg (0.27 mmol)5-(4-chloro-phenyl)-2-ethynyl-pyridine.

Yield: 10 mg (9.6% of theory). C₂₆H₂₅ClN₂ (M=400.956). Calc.: molpeak(M+H)⁺: 401/403 Found: molpeak (M+H)⁺: 401/403. HPLC retention time:6.94 min (method A).

EXAMPLE 3.235-(4-chloro-phenyl)-2-[4-(2-pyrrolidin-1-yl-ethyl)-phenylethynyl]-pyridine

3.23a 1-[2-(4-bromo-phenyl)-ethyl]-pyrrolidine

0.51 mL (4.23 mmol) 1,4-dibromobutane in 20 mL acetonitrile is addedslowly to a solution of 1.0 g (4.23 mmol) 4-bromo-phenethylaminehydrochloride, 1.8 g (13.0 mmol) K₂CO₃ and 200 mg (1.20 mmol) KI in 100mL acetonitrile at 75° C. and the reaction mixture is stirred for afurther 4 h at 75° C. The reaction solution is diluted with 100 mL waterand the aqueous phase is extracted with 100 mL EtOAc. The combinedorganic extracts are washed with saturated NaCl solution, the organicphase is dried over Na₂SO₄ and the solvent is eliminated i.vac. Furtherpurification is carried out by column chromatography on silica gel(EtOAc/MeOH/NH₃ 9:1:0.1)

Yield: 540 mg (50.2% of theory). C₁₂H₁₆BrN (M=254.172). Calc.: molpeak(M+H)⁺: 254/256 Found: molpeak (M+H)⁺: 254/256. R_(f) value: 0.54(silica gel, EtOAc/MeOH/NH₃ 9:1:0.1).

3.23b5-(4-chloro-phenyl)-2-[4-(2-pyrrolidin-1-yl-ethyl)-phenylethynyl]-pyridine

The product is obtained analogously to Example 3.16b from 60 mg (0.23mmol) 1-[2-(4-bromo-phenyl)-ethyl]-pyrrolidine and 50 mg (0.23 mmol)5-(4-chloro-phenyl)-2-ethynyl-pyridine.

Yield: 8 mg (8.7% of theory). C₂₅H₂₃ClN₂ (M=386.928). Calc.: molpeak(M+H)⁺: 387/389 Found: molpeak (M+H)⁺: 387/389. HPLC retention time:6.45 min (method A).

EXAMPLE 3.241-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-4-methyl-[1,4]diazepan

3.24a 1-(5-bromo-pyridin-2-yl)-4-methyl-[1,4]diazepan

1.5 g (5.29 mmol) 5-bromo-2-iodobenzene and 1.5 mL (11.7 mmol)1-methylhomopiperazine are heated to 170° C. for 1.5 h. After thereaction mixture has cooled 40 mL semisaturated NaHCO₃ solution and 100mL EtOAc are added. The organic phase is dried over Na₂SO₄ and thesolvent is eliminated i.vac. Further purification is carried out bycolumn chromatography on silica gel (EtOAc/MeOH/NH₃ 85:15:1).

Yield: 1.10 g (77.1% of theory). C₁₁H₁₆BrN₃ (M=270.174). Calc.: molpeak(M+H)⁺: 270/272 Found: molpeak (M+H)⁺: 270/272. R_(f) value: 0.57(silica gel, EtOAc/MeOH/NH₃ 8:2:0.2).

3.24b 1-(5-iodo-pyridin-2-yl)-4-methyl-[1,4]diazepan

Prepared according to general working method II from1-(5-bromo-pyridin-2-yl)-4-methyl-[1,4]diazepan (472 mg, 1.75 mmol).

Yield: 546 mg (98.5% of theory). C₁₁H₁₆IN₃ (M=317.175). HPLC retentiontime: 4.56 min (method A).

3.24c1-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-4-methyl-[1,4]diazepan

Prepared according to general working method I from1-(5-iodo-pyridin-2-yl)-4-methyl-[1,4]diazepan (237 mg, 0.75 mmol) and5-(4-chloro-phenyl)-2-ethynyl-pyridine (161 mg, 0.75 mmol).

Yield: 54 mg (17.9% of theory). C₂₄H₂₃ClN₄ (M=402.931). Calc.: molpeak(M+H)⁺: 403/405 Found: molpeak (M+H)⁺: 403/405. HPLC retention time:6.79 min (method A).

EXAMPLE 3.251-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-4-methyl-piperazine

3.25a 1-(5-bromo-pyridin-2-yl)-4-methyl-piperazine

The product is obtained analogously to Example 3.24a is from 1.5 g (5.28mmol) 5-bromo-2-iodopyridine and 1.3 mL (11.7 mmol) N-methylpiperazine.

Yield: 1.15 g (85.1% of theory). C₁₀H₁₄BrN₃ (M=256.147). Calc.: molpeak(M+H)⁺: 256/258 Found: molpeak (M+H)⁺: 256/258. R_(f) value: 0.50(silica gel, EtOAc/MeOH/NH₃ 9:1:0.1).

3.25b 1-(5-iodo-pyridin-2-yl)-4-methyl-piperazine

Prepared according to general working method II from1-(5-bromo-pyridin-2-yl)-4-methyl-piperazine (500 mg, 1.95 mmol).

Yield: 532 mg (89.9% of theory). C₁₀H₁₄IN₃ (M=303.148). HPLC retentiontime: 4.59 min (method A).

3.25c1-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-4-methyl-piperazine

Prepared according to general working method I from1-(5-iodo-pyridin-2-yl)-4-methyl-piperazine (235 mg, 0.78 mmol) and5-(4-chloro-phenyl)-2-ethynyl-pyridine (167 mg, 0.78 mmol).

Yield: 15 mg (5.0% of theory). C₂₃H₂₁ClN₄ (M=388.904). Calc.: molpeak(M+H)⁺: 389/391 Found: molpeak (M+H)⁺: 389/391. HPLC retention time:6.79 min (method A).

EXAMPLE 3.26(1S,4S)-2-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-6-methyl-2,6-diaza-bicyclo[2.2.1]heptane

3.26a(1S,4S)-2-(5-bromo-pyridin-2-yl)-6-methyl-2,6-diaza-bicyclo[2.2.1]heptane

A solution of 300 mg (1.10 mmol)(1S,4S)-2-methyl-2,5-diazabicylo[2.2.1]heptane dihydrobromide, 0.75 mL(4.40 mmol) ethyldiisopropylamine and 270 mg (1.11 mmol)2,5-dibromopyridine in 1.5 mL n-butanol are stirred for 18 h at 115° C.The solvent is eliminated i.vac., the residue is combined with 10 mLEtOAc and acidified with 1 M HCl. The aqueous phase is twice madealkaline with 2 M K₂CO₃ solution and extracted with 30 mL EtOAc. Thecombined organic extracts are dried over Na₂SO₄ and the solvent iseliminated i.vac.

Yield: 70 mg (23.8% of theory). C₁₁H₁₄BrN₃ (M=268.158). HPLC retentiontime: 4.07 min (method A). R_(f) value: 0.05 (silica gel, EtOAc/MeOH/NH₃9:1:0.1).

3.26b(1S,4S)-2-(5-iodo-pyridin-2-yl)-6-methyl-2,6-diaza-bicyclo[2.2.1]heptane

Prepared according to general working method II from(1S,4S)-2-(5-bromo-pyridin-2-yl)-6-methyl-2,6-diaza-bicyclo[2.2.1]heptane(70 mg, 0.26 mmol).

Yield: 45 mg (54.7% of theory). C₁₁H₁₄IN₃ (M=315.159). HPLC retentiontime: 4.18 min (method A). R_(f) value: 0.06 (silica gel, EtOAc/MeOH/NH₃9:1:0.1).

3.26c(1S,4S)-2-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-6-methyl-2,6-diaza-bicyclo[2.2.1]heptane

Prepared according to general working method I from(1S,4S)-2-(5-iodo-pyridin-2-yl)-6-methyl-2,6-diaza-bicyclo[2.2.1]heptane(45 mg, 0.14 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (51 mg,0.24 mmol).

Yield: 6 mg (10.3% of theory). C₂₄H₂₁ClN₄ (M=400.915). Calc.: molpeak(M+H)⁺: 401/403 Found: molpeak (M+H)⁺: 401/403. HPLC retention time:6.44 min (method A).

EXAMPLE 3.27{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-methyl-(2-pyrrolidin-1-yl-ethyl)-amine

3.27a (5-bromo-pyridin-2-yl)-methyl-(2-pyrrolidin-1-yl-ethyl)-amine

The product is obtained analogously to Example 3.24a (reaction time 2.5h) from 11.5 g (40.5 mmol) 5-bromo-2-iodopyridine and 6.3 mL (11.7 mmol)methyl-(2-pyrrolidin-1-yl-ethyl)-amine.

Yield:, 4.0 g (34.8% of theory). C₁₂H₁₈BrN₃ (M=284.201). Calc.: molpeak(M+H)⁺: 284/286 Found: molpeak (M+H)⁺: 284/286. R_(f) value: 0.37(silica gel, DCM/MeOH/NH₃ 9:1:0.1). HPLC retention time: 5.09 min(method A).

3.27b (5-iodo-pyridin-2-yl)-methyl-(2-pyrrolidin-1-yl-ethyl)-amine

Prepared according to general working method II from(5-bromo-pyridin-2-yl)-methyl-(2-pyrrolidin-1-yl-ethyl)-amine (1.1 g,3.87 mmol).

Yield: 1.0 g (81.1% of theory). C₁₂H₁₈IN₃ (M=331.202). Calc.: molpeak(M+H)⁺: 332 Found: molpeak (M+H)⁺: 332. HPLC retention time: 5.19 min(method A).

3.27c{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-methyl-(2-pyrrolinin-1-yl-ethyl)-amine

Prepared according to general working method I from(5-iodo-pyridin-2-yl)-methyl-(2-pyrrolidin-1-yl-ethyl)-amine (100 mg,0.30 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (65 mg, 0.30mmol).

Yield: 43 mg (34.2% of theory). C₂₅H₂₅ClN₄ (M=416.958). Calc.: molpeak(M+H)⁺: 417/419 Found: molpeak (M+H)⁺: 417/419. R_(f) value: 0.25 (Alox,cyc/EtOAc 2:1). HPLC retention time: 7.57 min (method A).

EXAMPLE 3.28(1-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-pyrrolidin-3-yl)-dimethyl-amine

3.28a [1-(5-bromo-pyridin-2-yl)-pyrrolidin-3-yl]-dimethyl-amine

A solution of 215 mg (0.88 mmol) 2,5-dibromobenzene, 100 mg (0.88 mmol)3-(dimethylamino)-pyrrolidine and 0.60 mL (3.51 mmol)ethyidiisopropylamine in 0.5 mL n-butanol is stirred for 30 min in themicrowave at 150° C. The solvent is eliminated i.vac. and the residue istaken up in 20 mL EtOAc and 10 mL water. The aqueous phase is acidifiedwith 1 M HCl. The phases are separated and then the aqueous phase ismade alkaline with 2 M Na₂CO₃ solution and extracted with 40 mL EtOAc.The organic phase is dried over Na₂SO₄ and the solvent is eliminatedi.vac.

Yield: 179 mg (75.6% of theory). C₁₁H₁₆BrN₃ (M=270.174). Calc.: molpeak(M+H)⁺: 270/272 Found: molpeak (M+H)⁺: 270/272. R_(f) value: 0.30(silica gel, EtOAc/MeOH/NH₃ 9:1:0.1).

3.28b [1-(5-iodo-pyridin-2-yl)-pyrrolidin-3-yl]-dimethyl-amine

Prepared according to general working method II from[1-(5-bromo-pyridin-2-yl)-pyrrolidin-3-yl]-dimethyl-amine (160 mg, 0.59mmol).

Yield: 168 mg (89.5% of theory). C₁₁H₁₆IN₃ (M=317.175). Calc.: molpeak(M+H)⁺: 318 Found: molpeak (M+H)⁺: 318. HPLC retention time: 3.56 min(method A).

3.28c(1-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-pyrrolidin-3-yl)-dimethyl-amine

Prepared according to general working method I from[1-(5-iodo-pyridin-2-yl)-pyrrolidin-3-yl]-dimethyl-amine (160 mg, 0.50mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (108 mg, 0.50 mmol).

Yield: 8 mg (3.9% of theory). C₂₄H₂₃ClN₄ (M=402.931). Calc.: molpeak(M+H)⁺: 403/405 Found: molpeak (M+H)⁺: 403/405. HPLC retention time:6.37 min (method A).

EXAMPLE 3.29{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-(2-pyrrolidin-1-yl-ethyl)-amine

3.29a (5-bromo-pyridin-2-yl)-(2-pyrrolidin-1-yl-ethyl)-amine

13.8 g (100.0 mmol) K₂CO₃, 79 mg (0.12 mmol)2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and 28 mg (0.12 mmol)Pd(OAc)₂ are added successively to a solution of 1.5 g (6.33 mmol)2,5-dibromopyridine and 0.98 mL (7.60 mmol) 1-(2-aminoethyl)-pyrrolidinein 60 mL toluene. The reaction is refluxed for 40 h. The solvent iseliminated i.vac. and the residue is taken up in 150 mL EtOAc and 100 mLwater. The organic phase is dried over Na₂SO₄ and the solvent iseliminated i.vac. Purification is carried out by column chromatographyon silica gel (gradient: EtOAc/MeOH/NH₃ 19:1:0.1 to EtOAc/MeOH/NH₃9:1:0.1).

Yield: 145 mg (8.5% of theory). C₁₁H₁₆BrN₃ (M=270.174). Calc.: molpeak(M+H)⁺: 270/272 Found: molpeak (M+H)⁺: 270/272. R_(f) value: 0.05(silica gel, EtOAc/MeOH/NH₃ 9:1:0.1).

3.29b{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-(2-pyrrolidin-1-yl-ethyl)-amine

The product is obtained analogously to Example 3.16b is from 90 mg (0.33mmol) (5-bromo-pyridin-2-yl)-(2-pyrrolidin-1-yl-ethyl)-amine and 88 mg(0.41 mmol) 5-(4-chloro-phenyl)-2-ethynyl-pyridine.

Yield: 4 mg (5.8% of theory). C₂₄H₂₃ClN₄ (M=402.931). Calc.: molpeak(M+H)⁺: 403/405 Found: molpeak (M+H)⁺: 403/405. HPLC retention time:6.71 min (method A).

EXAMPLE 3.30N-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-N-(2-pyrrolidin-yl-ethyl)-acetamide

45 μL (0.48 mmol) acetic anhydride is added to a solution of 89 mg (0.22mmol){5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-(2-pyrrolidin-1-yl-ethyl)-aminein 2 mL DCM. The reaction solution is stirred for 16 h at RT. Thesolvent is eliminated i.vac. and further purification is carried out byHPLC-MS.

Yield: 62 mg (63.0% of theory). C₂₆H₂₅ClN₄O (M=444.968). Calc.: molpeak(M+H)⁺: 445/447 Found: molpeak (M+H)⁺: 445/447. R_(f) value: 0.38 (Alox,cyc/EtOAc 1:1).

EXAMPLE 3.31{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-(2-piperidin-1-yl-ethyl)-amine

3.31a (5-bromo-pyridin-2-yl)-(2-piperidin-1-yl-ethyl)-amine

800 mg (3.38 mmol) 2,5-dibrombenzene and 1.0 g (7.80 mmol)N-(2-aminoethyl)piperidine are heated to 170° C. for 45 min. After thereaction mixture has cooled 80 mL EtOAc are added and filtered. Thefiltrate is washed twice with 40 mL saturated NaHCO₃ solution and driedover MgSO₄. After the desiccant and solvent have been eliminated theresidue is purified by chromatography (silica gel, EtOAc/MeOH/NH₃85:15:2).

Yield: 720 mg (75.0% of theory). C₁₂H₁₈BrN₃ (M=284.201). Calc.: molpeak(M+H)⁺: 284/286 Found: molpeak (M+H)⁺: 284/286. R_(f) value: 0.30(silica gel, EtOAc/MeOH/NH₃ 9:1:0.1).

3.31b (5-iodo-pyridin-2-yl)-(2-piperidin-1-yl-ethyl)-amine

Prepared according to general working method II from(5-bromo-pyridin-2-yl)-(2-piperidin-1-yl-ethyl)-amine (720 mg, 2.53mmol).

Yield: 750 mg (89.4% of theory). C₁₂H₁₈IN₃ (M=331.202). Calc.: molpeak(M+H)⁺: 332 Found: molpeak (M+H)⁺: 332. HPLC retention time: 4.32 min(method A).

3.31c{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-(2-piperidin-1-yl-ethyl)-amine

Prepared according to general working method I from(5-iodo-pyridin-2-yl)-(2-piperidin-1-yl-ethyl)-amine (397 mg, 1.20 mmol)and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (256 mg, 1.20 mmol).

Yield: 230 mg (46.0% of theory). C₂₅H₂₅ClN₄ (M=416.958). Calc.: molpeak(M+H)⁺: 417/419 Found: molpeak (M+H)⁺: 417/419. R_(f) value: 0.55(silica gel, EtOAc/MeOH/NH₃ 9:1:0.1). HPLC retention time: 7.26 min(method A).

EXAMPLE 3.325′-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-3-pyrrolidin-1-yl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl

3.32a 5′-bromo-3-pyrrolidin-1-yl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl

The product is obtained analogously to Example 3.31a (reaction time: 35min at 160° C.) from 2.37 g (10.0 mmol) 2,5-dibromopyridine and 1.6 g(10.4 mmol) 3-pyrrolidin-1-yl-piperidine.

Yield: 700 mg (21.8% of theory). C₁₄H₂₀BrN₃ (M=310.240). Calc.: molpeak(M+H)⁺: 310/312 Found: molpeak (M+H)⁺: 310/312. HPLC retention time:5.06 min (method B).

3.32b 5′-iodo-3-pyrrolidin-1-yl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl

Prepared according to general working method II from5′-bromo-3-pyrrolidin-1-yl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl (700mg, 2.26 mmol).

Yield: 700 mg (86.9% of theory). C₁₄H₂₀IN₃ (M=357.240). Calc.: molpeak(M+H)⁺: 358 Found: molpeak (M+H)⁺: 358. HPLC retention time: 5.20 min(method A).

3.32c5′-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-3-pyrrolidin-1-yl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl

Prepared according to general working method I from5′-iodo-3-pyrrolidin-1-yl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl (179mg, 0.50 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (107 mg, 0.50mmol).

Yield: 120 mg (54.2% of theory). C₂₇H₂₇ClN₄ (M=442.996). Calc.: molpeak(M+H)⁺: 443/445 Found: molpeak (M+H)⁺: 443/445. R_(f) value: 0.38(silica gel, DCM/MeOH/NH₃ 9:1:0.1). HPLC retention time: 7.40 min(method A).

EXAMPLE 3.331′-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-[1,3′]bipyrrolidinyl

3.33a 1′-benzyl-[1,3′]bipyrrolidinyl

3.82 g (18.0 mmol) NaBH(OAc)₃ are added to a solution of 1.23 mL (15.0mmol) pyrrolidine and 2.41 mL (15.0 mmol) N-benzylpyrrolidinone in 100mL THF and acidified with 2 mL acetic acid. The reaction is stirredovernight at RT. The reaction solution is combined with 200 mL saturatedNaHCO₃ solution and extracted twice with 200 mL EtOAc. The organic phaseis dried over MgSO₄ and the solvent is eliminated i.vac. Thepurification is carried out by column chromatography on silica gel(EtOAc/MeOH/NH₃ 8:2:0.2).

Yield: 1.80 g (52.1% of theory). C₁₅H₂₂N₂ (M=230.356). Calc.: molpeak(M+H)⁺: 231 Found: molpeak (M+H)⁺: 231. R_(f) value: 0.05 (silica gel,EtOAc/MeOH/NH₃ 9:1:0.1).

3.33b [1,3′]bipyrrolidinyl

180 mg 10% Pd/C are added to a solution of 1.80 g (7.42 mmol)1′-benzyl-[1,3′]bipyrrolidinyl in 80 mL MeOH. The reaction solution isstirred for 5 h at RT and at 3 bar H₂. Another 180 mg 10% Pd/C are addedand after 4 h 100 mg palladium hydroxide are added. The reaction isstirred for a further 6 h at RT and at 3 bar H₂. The catalyst is suctionfiltered and the solvent is eliminated i.vac.

Yield: 900 mg (86.5% of theory). C₈H₁₆N₂ (M=140.230). R_(f) value: 0.05(silica gel, EtOAc/MeOH/NH₃ 8:2:0.2).

3.33c 1′-(5-bromo-pyridin-2-yl)-[1,3′]bipyrrolidinyl

The product is obtained analogously to Example 3.31a (reaction time: 60min at 170° C.) from 1.52 g (6.40 mmol) 2,5-dibromopyridine and 0.90 g(6.42 mmol) [1,3′]bipyrrolidinyl.

Yield: 700 mg (36.8% of theory). C₁₃H₁₈BrN₃ (M=296.213). Calc.: molpeak(M+H)⁺: 296/298 Found: molpeak (M+H)⁺: 296/298. R_(f) value: 0.42(silica gel, EtOAc/MeOH/NH₃ 9:1:0.1).

3.33d 1′-(5-iodo-pyridin-2-yl)-[1,3′]bipyrrolidinyl

Prepared according to general working method II from1′-(5-bromo-pyridin-2-yl)-[1,3′]bipyrrolidinyl (700 mg, 2.36 mmol).

Yield: 650 mg (80.1% of theory). C₁₃H₁₈IN₃ (M=343.213). Calc.: molpeak(M+H)⁺: 344 Found: molpeak (M+H)⁺: 344. HPLC retention time: 3.95 min(method A).

3.33e1′-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-[1,3′]bipyrrolidinyl

Prepared according to general working method I from1′-(5-iodo-pyridin-2-yl)-[1,3′]bipyrrolidinyl (172 mg, 0.50 mmol) and5-(4-chloro-phenyl)-2-ethynyl-pyridine (107 mg, 0.50 mmol).

Yield: 65 mg (30.3% of theory). C₂₆H₂₅ClN₄ (M=428.969). Calc.: molpeak(M+H)⁺: 429/431 Found: molpeak (M+H)⁺: 429/431. R_(f) value: 0.50(silica gel, EtOAc/MeOH/NH₃ 9:1:0.1) HPLC retention time: 6.71 min(method A).

EXAMPLE 3.34{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-(2-pyrrolidin-1-yl-propyl)-amine

3.34a N-(5-bromo-pyridin-2-yl)-2-chloro-propionamide

2.14 mL (22.0 mmol) 2-chloropropionic acid chloride in 5 mL DCM is addeddropwise to a solution of 3.46 g (20.0 mmol) 2-amino-5-bromopyridine and6.12 mL (44.0 mmol) triethylamine in 80 mL DCM at 0° C. The ice bath isremoved and the reaction solution is stirred for a further 1.5 h at RT.Another 0.40 mL (4.12 mmol) 2-chloropropionic acid chloride is added andthe solution is stirred for a further hour at RT. The reaction mixtureis combined with 80 mL water, washed once with 80 mL saturated NaClsolution and dried over MgSO₄. The solvent is eliminated i.vac. and theresidue is triturated with a little EtOAc, suction filtered and dried.

Yield: 3.50 g (66.4% of theory). C₈H₈BrClN₂O (M=263.523). Calc.: molpeak(M+H)⁺: 263/265/267 Found: molpeak (M+H)⁺: 263/265/267. R_(f) value:0.85 (silica gel, PE/EtOAc 6:4).

3.34b N-(5-bromo-pyridin-2-yl)-2-pyrrolidin-1-yl-propionamide

4.01 g (29.0 mmol) K₂CO₃ and 1.19 mL (14.5 mmol) pyrrolidine are addedsuccessively to a solution of 3.5 g (13.3 mmol)N-(5-bromo-pyridin-2-yl)-2-chloro-propionamide in 50 mL DMF. Thereaction is stirred for 3 days at RT and combined with 150 mL water. Theaqueous phase is extracted twice with EtOAc and the organic phase isdried over MgSO₄. After the desiccant and solvent have been eliminatedthe residue is purified by chromatography (silica gel, gradient:PE/EtOAc 4:6 after EtOAc).

Yield: 1.80 g (45.4% of theory). C₁₂H₁₆BrN₃O₃ (M=298.185). Calc.:molpeak (M+H)⁺: 298/300 Found: molpeak (M+H)⁺: 298/300. HPLC retentiontime: 4.21 min (method A).

3.34c (5-bromo-pyridin-2-yl)-(2-pyrrolidin-1-yl-propyl)-amine

Under a nitrogen atmosphere 6.00 mL (6.00 mmol) 1 M lithium aluminiumhydride solution in THF are added to a solution, cooled to 0° C., of 1.8g (6.04 mmol) N-(5-bromo-pyridin-2-yl)-2-pyrrolidin-1-yl-propionamide in30 mL THF, in such a way that the internal temperature does not exceed4° C. The reaction solution is stirred for a further 20 min at 0° C.EtOAc is carefully added, the aluminium complex is decomposed with 0.2mL water, then with 0.2 mL 15% sodium hydroxide solution solution andfinally with 0.6 mL water. The precipitate formed is suction filteredand the filtrate is diluted with 50 mL EtOAc. The organic phase iswashed with 30 mL saturated NaHCO₃ solution and dried over MgSO₄. Thesolvent is eliminated i.vac. and further purification is carried out bycolumn chromatography on silica gel (EtOAc/MeOH/NH₃ 9:1:0.1).

Yield: 700 mg (40.8% of theory). C₁₂H₁₈BrN₃ (M=284.201). Calc.: molpeak(M+H)⁺: 284/286 Found: molpeak (M+H)⁺: 284/286. R_(f) value: 0.32(silica gel, EtOAc/MeOH/NH₃ 9:1:0.1). HPLC retention time: 4.63 min(method A).

3.34d (5-iodo-pyridin-2-yl)-(2-pyrrolidin-1-yl-propyl)-amine

Prepared according to general working method II from(5-bromo-pyridin-2-yl)-(2-pyrrolidin-1-yl-propyl)-amine (600 mg, 2.11mmol).

Yield: 560 mg (80.1% of theory).

3.34e{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-(2-pyrrolidin-1-yl-propyl)-amine

Prepared according to general working method I from(5-iodo-pyridin-2-yl)-(2-pyrrolidin-1-yl-propyl)-amine (250 mg, 0.76mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (165 mg, 0.77 mmol).

Yield: 95 mg (29.5% of theory). C₂₅H₂₅ClN₄ (M=416.958) Calc.: molpeak(M+H)⁺: 417/419 Found: molpeak (M+H)⁺: 417/419. HPLC retention time:7.19 min (method A).

EXAMPLE 3.35N-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-2-pyrrolidin-1-yl-propionamide

3.35a 4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenylamine

Prepared according to general working method I from 4-iodoaniline (732mg, 3.28 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (700 mg, 3.28mmol).

Yield: 440 mg (44.1% of theory). C₁₉H₁₃ClN₂ (M=304.782). Calc.: molpeak(M+H)⁺: 305/307 Found: molpeak (M+H)⁺: 305/307. HPLC retention time:5.70 min (method A).

3.35bN-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-2-pyrrolidin-1-yl-propionamide

0.18 mL (1.31 mmol) triethylamine and 269 mg (0.84 mmol) TBTU are addedsuccessively to a solution of 100 mg (0.70 mmol)2-pyrrolidin-1-yl-propionic acid in 10 mL THF. The solution is stirredfor 1 h at RT and then 200 mg (0.66 mmol)4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenylamine are added. Thereaction solution is stirred overnight at RT. The reaction isincomplete. Therefore 100 mg (0.70 mmol) 2-pyrrolidin-1-yl-propionicacid in 10 mL THF is added to the reaction mixture (activated for 1 h bystirring with 0.18 mL (1.31 mmol) triethylamine and 269 mg (0.84 mmol)TBTU). The reaction solution is stirred for a further 16 h and dilutedwith NaHCO₃ solution. The aqueous phase is extracted with EtOAc and theorganic phase is dried over MgSO₄. The solvent is eliminated i.vac. andfurther purification is carried out by column chromatography on silicagel (EtOAc/MeOH/NH₃ 8:2:0.2).

Yield: 40 mg (14.2% of theory). C₂₆H₂₄ClN₃O (M=429.954). Calc.: molpeak(M+H)⁺: 430/432 Found: molpeak (M+H)⁺: 430/432. HPLC retention time:7.29 min (method A).

EXAMPLE 3.36N-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-2-pyrrolidin-1-yl-acetamide

The product is obtained analogously to Example 3.35b from 200 mg (0.66mmol) 4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenylamine and 100 mg(0.77 mmol) pyrrolidin-1-yl-acetic acid.

Yield: 5 mg (1.8% of theory). C₂₅H₂₂ClN₃O (M=415.927). Calc.: molpeak(M+H)⁺: 416/418 Found: molpeak (M+H)⁺: 416/418. HPLC retention time:6.75 min (method B).

EXAMPLE 3.375-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-1-(2-pyrrolidin-1-yl-ethyl)-1,3-dihydro-benzimidazol-2-one

3.37a (4-bromo-2-nitro-phenyl)-(2-pyrrolidin-1-yl-ethyl)-amine

4.42 g (32.0 mmol) K₂CO₃ are added to a solution of 5.00 g (22.7 mmol)2-bromo-5-fluoronitrobenzene and 2.59 g (22.7 mmol)1-(2-amino)-pyrrolidine in 20 mL acetonitrile. The reaction solution isstirred overnight at RT. The solution is filtered and the solvent iseliminated i.vac. The purification is carried out by columnchromatography on silica gel (gradient: DCM to DCM/MeOH 9:1).

Yield: 5.90 g (82.6% of theory). C₁₂H₁₆BrN₃O₂ (M=314.184). Calc.:molpeak (M+H)⁺: 314/316 Found: molpeak (M+H)⁺: 314/316. R_(f) value:0.40 (silica gel, DCM/MeOH 9:1).

3.37b 4-bromo-N¹-(2-pyrrolidin-1-yl-ethyl)-benzene-1,2-diamine

100 mg Raney Nickel are added to a solution of 1.00 g (3.18 mmol)(4-bromo-2-nitro-phenyl)-(2-pyrrolidin-1-yl-ethyl)-amine in 100 mL MeOH.The reaction solution is stirred for 15 min at 3 bar H₂ and RT. Afterfiltration the solvent is eliminated i.vac. and the product is furtherreacted without purification.

Yield: 850 mg (94.0% of theory). C₁₂H₁₈BrN₃ (M=284.201). Calc.: molpeak(M+H)⁺: 284/286 Found: molpeak (M+H)⁺: 284/286. HPLC retention time:4.56 min (method A).

3.37c 5-bromo-1-(2-pyrrolidin-1-yl-ethyl)-1,3-dihydro-benzimidazol-2-one

600 mg (3.70 mmol) CDI are added to a solution of 853 mg (3.00 mmol)4-bromo-N′-(2-pyrrolidin-1-yl-ethyl)-benzene-1,2-diamine in 20 mL THF atRT. The reaction solution is heated to 40° C. and stirred for 30 min atthis temperature. A further 600 mg (3.70 mmol) CDI are added and thereaction is stirred for a further 30 min at 40° C. The solution isdiluted with semisaturated NaHCO₃ solution and the aqueous phase isextracted twice with EtOAc. The organic phase is dried over MgSO₄ andthe solvent is eliminated i.vac. The residue is triturated withacetonitrile, the precipitate is filtered and dried in the air.

Yield: 500 mg (53.7% of theory). C₁₃H₁₆BrN₃O (M=310.196). Calc.: molpeak(M+H)⁺: 310/312 Found: molpeak (M+H)⁺: 310/312. HPLC retention time:4.30 min (method A).

3.37d 5-iodo-1-(2-pyrrolidin-1-yl-ethyl)-1,3-dihydro-benzimidazol-2-one

Prepared according to general working method II from5-bromo-1-(2-pyrrolidin-1-yl-ethyl)-1,3-dihydro-benzimidazol-2-one (150mg, 0.48 mmol).

Yield: 140 mg (81.0% of theory). C₁₃H₁₆IN₃O (M=357.196). Calc.: molpeak(M+H)⁺: 358 Found: molpeak (M+H)⁺: 358. HPLC retention time: 4.53 min(method A).

3.37e5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-1-(2-pyrrolidin-1-yl-ethyl)-1,3-dihydro-benzimidazol-2-one

Prepared according to general working method II from5-iodo-1-(2-pyrrolidin-1-yl-ethyl)-1,3-dihydro-benzimidazol-2-one (140mg, 0.39 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (83 mg, 0.39mmol).

Yield: 7 mg (3.7% of theory). C₂₆H₂₃ClN₄O (M=442.952). Calc.: molpeak(M+H)⁺: 443/445 Found: molpeak (M+H)⁺: 443/445. HPLC retention time:6.78 min (method A).

EXAMPLE 3.385-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-3-methyl-1-(2-pyrrolidin-1-yl-ethyl)-1,3-dihydro-benzoimidazol-2-one

3.38a5-bromo-3-methyl-1-(2-pyrrolidin-1-yl-ethyl)-1,3-dihydro-benzimidazol-2-one

73 mg (0.65 mmol) potassium-tert-butoxide are added to a solution of 200mg (0.65 mmol)5-bromo-1-(2-pyrrolidin-1-yl-ethyl)-1,3-dihydro-benzimidazol-2-one in 4mL DMSO at RT. The reaction solution is stirred for 30 min and then 40μL (0.65 mmol) iodomethane are added and stirred for a further 30 min.The mixture is combined with semisaturated NaHCO₃ solution and theaqueous phase is extracted twice with 30 mL EtOAc. The organic phase isdried over MgSO₄ and the solvent is eliminated i.vac.

Yield: 180 mg (86.1% of theory). C₁₄H₁₈BrN₃O (M=324.223). Calc.: molpeak(M+H)⁺: 324/326 Found: molpeak (M+H)⁺: 324/326. HPLC retention time:4.69 min (method B).

3.38b5-iodo-3-methyl-1-(2-pyrrolidin-1-yl-ethyl)-1,3-dihydro-benzimidazol-2-one

Prepared according to general working method II from5-bromo-3-methyl-1-(2-pyrrolidin-1-yl-ethyl)-1,3-dihydro-benzimidazol-2-one(160 mg, 0.49 mmol).

Yield: 120 mg (65.6% of theory). C₁₄H₁₈IN₃O (M=371.223). Calc.: molpeak(M+H)⁺: 372 Found: molpeak (M+H)⁺: 372. HPLC retention time: 5.02 min(method A).

3.38c5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-3-methyl-1-(2-pyrrolidin-1-yl-ethyl)-1,3-dihydro-benzimidazol-2-one

Prepared according to general working method I from5-iodo-3-methyl-1-(2-pyrrolidin-1-yl-ethyl)-1,3-dihydro-benzimidazol-2-one(120 mg, 0.32 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (68 mg,0.32 mmol).

Yield: 15 mg (9.8% of theory). C₂₇H₂₅ClN₄O (M=456.980). Calc.: molpeak(M+H)⁺: 457/459 Found: molpeak (M+H)⁺: 457/459. HPLC retention time:7.11 min (method A).

EXAMPLE 3.396-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-3-(2-pyrrolidin-1-yl-ethyl)-3H-imidazo[4,5-b]pyridine

3.39a (5-bromo-3-nitro-pyridin-2-yl)-(2-pyrrolidin-1-yl-ethyl)-amine

0.86 mL (5.05 mmol) ethyldiiopropylamine are added to a solution of 600mg (2.53 mmol) 5-bromo-2-chloro-3-nitropyridine and 0.32 mL (2.53 mmol)1-(2-aminoethyl)-pyrrolidine in 3 mL n-butanol. The reaction is heatedto 50° C. and stirred for one hour at this temperature. The solvent iseliminated i.vac. and the residue is combined with 40 mL water andacidified with 1 M HCl. The aqueous phase is extracted with 20 mL EtOAcand the aqueous phase is then made alkaline with saturated K₂CO₃solution. The aqueous phase is extracted with 40 mL EtOAc. The organicphase is dried over Na₂SO₄ and the solvent is eliminated i.vac.

Yield: 692 mg (86.9% of theory). C₁₁H₁₅BrN₄O₂ (M=315.172). Calc.:molpeak (M+H)⁺: 315/317 Found: molpeak (M+H)⁺: 315/317. HPLC retentiontime: 5.00 min (method A). R_(f) value: 0.08 (silica gel, cyc/EtOAc2:1).

3.39b 5-bromo-N²-(2-pyrrolidin-1-yl-ethyl)-pyridine-2,3-diamine

2.44 g (10.8 mmol) Zinn(II)chloride dihydrate and 2.20 g (26.2 mmol)NaHCO₃ are added to a solution of 680 mg (2.16 mmol)(5-bromo-3-nitro-pyridin-2-yl)-(2-pyrrolidin-1-yl-ethyl)-amine in 40 mLEtOAc at RT. The reaction is refluxed for 1.5 h and then diluted with 20mL water. The aqueous phase is acidified with 1 M HCl and separated offfrom the organic phase. The aqueous phase is made alkaline withsaturated K₂CO₃ solution and extracted twice with 40 mL EtOAc. Theorganic phase is dried over Na₂SO₄ and the solvent is eliminated i.vac.

Yield: 479 mg (77.8% of theory). C₁₁H₁₇BrN₄ (M=285.189). Calc.: molpeak(M+H)⁺: 285/287 Found: molpeak (M+H)⁺: 285/287. HPLC retention time: 3.9min (method A).

3.39c 6-bromo-3-(2-pyrrolidin-1-yl-ethyl)-3H-imidazo[4,5-b]pyridine

A solution of 470 mg (1.65 mmol)5-bromo-N²-(2-pyrrolidin-1-yl-ethyl)-pyridine-2,3-diamine in 10 mLformic acid is refluxed for 1.5 h. The mixture is made alkaline withsaturated K₂CO₃ solution and extracted with 40 mL EtOAc. The organicphase is dried over Na₂SO₄ and the solvent is eliminated i.vac.

Yield: 466 mg (95.8% of theory). C₁₂H₁₅BrN₄ (M=295.184). Calc.: molpeak(M+H)⁺: 295/297 Found: molpeak (M+H)⁺: 295/297. HPLC retention time: 4.0min (method A).

3.39d 6-iodo-3-(2-pyrrolidin-1-yl-ethyl)-3H-imidazo[4,5-b]pyridine

Prepared according to general working method II from6-bromo-3-(2-pyrrolidin-1-yl-ethyl)-3H-imidazo[4,5-b]pyridine (450 mg,1.52 mmol).

Yield: 510 mg (97.8% of theory). C₁₂H₁₅IN₄ (M=342.185). Calc.: molpeak(M+H)⁺: 343 Found: molpeak (M+H)⁺: 343. HPLC retention time: 4.08 min(method A). R_(f) value: 0.09 (silica gel, EtOAc/MeOH/NH₃ 9:1:0.1).

3.39e6-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-3-(2-pyrrolidin-1-yl-ethyl)-3H-imidazo[4,5-b]pyridine

Prepared according to general working method I from6-iodo-3-(2-pyrrolidin-1-yl-ethyl)-3H-imidazo[4,5-b]pyridine (300 mg,0.88 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (187 mg, 0.88mmol).

Yield: 67 mg (17.9% of theory). C₂₅H₂₂ClN₅ (M=427.941). Calc.: molpeak(M+H)⁺: 428/430 Found: molpeak (M+H)⁺: 428/430. R_(f) value: 0.41(silica gel, DCM/MeOH/NH₃ 9:1:0.1). HPLC retention time: 6.52 min(method A).

EXAMPLE 3.405-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-pyrrolidin-1-ylmethyl-1H-benzimidazole

3.40a (5-nitro-1H-benzimidazol-2-yl)-methanol

6.2 g (81.5 mmol) glycolic acid is added to a solution of 6.24 g (40.8mmol) 4-nitro-o-phenylenediamine in 80 mL semiconcentrated HCl. Thereaction solution is refluxed for 4 h and the solvent is eliminatedi.vac. The residue is taken up in water and made basic with 2 N NaOH.The product precipitates out and is stirred for another 1 hour in theice bath. The precipitate is suction filtered and washed successivelywith water and PE. The product is dried at 40° C. This still contains40% 4-nitro-o-phenylenediamine. It is again taken up in semiconcentratedHCl and after the addition of 6.5 mL glycolic acid (57% in water) it isrefluxed for 3 h and heated for a further 12 h at 80° C. The solvent iseliminated i.vac. and the residue is dissolved in water and madealkaline with 6 N NaOH, during which time the product is precipitated.The precipitate is suction filtered and washed successively with waterand PE. The product is dried in the circulating air dryer at 50° C.

Yield: 6.40 g (81.3% of theory). C₈H₇N₃O₃ (M=193.163). Calc.: molpeak(M+H)⁺: 194 Found: molpeak (M+H)⁺: 194. R_(f) value: 0.13 (silica gel,DCM/MeOH/NH₃ 9:1:0.1).

3.40b 2-chloromethyl-5-nitro-1H-benzimidazole

20 mL (275 mmol) thionyl chloride are added slowly to a solution of 6.4g (33.1 mmol) (5-nitro-1H-benzimidazol-2-yl)-methanol in 100 mL DCM at10° C. The reaction is stirred for 1 h at RT and the solvent iseliminated i.vac. The residue is triturated with DCM, suction filtered,washed with DCM and ether and dried in the circulating air dryer at 35°C.

Yield: 7.01 g (100% of theory). C₈H₆ClN₃O₃ (M=211.609). Calc.: molpeak(M+H)⁺: 212/214 Found: molpeak (M+H)⁺: 212/214. HPLC retention time: 4.1min (method B).

3.40c 5-nitro-2-pyrrolidin-1-ylmethyl-1H-benzimidazole

9.47 mL (113 mmol) pyrrolidine are added to a solution of 6.00 g (28.4mmol) 2-chloromethyl-5-nitro-1H-benzimidazole in 100 mL DCM. Thereaction is stirred overnight at RT. The reaction solution is washedfour times with water. The organic phase is dried over MgSO₄ and thesolvent is eliminated i.vac.

Yield: 5.50 g (78.8% of theory). C₁₂H₁₄N₄O₂ (M=246.271). Calc.: molpeak(M+H)⁺: 247 Found: molpeak (M+H)⁺: 247. R_(f) value: 0.22 (silica gel,EtOAc/MeOH 9:1).

3.40d 2-pyrrolidin-1-ylmethyl-1H-benzimidazol-5-ylamine

1.00 g Raney nickel is added to a solution of 5.50 g (22.3 mmol)5-nitro-2-pyrrolidin-1-ylmethyl-1H-benzimidazole in 50 mL MeOH. Thereaction solution is stirred for 30 h at 3 bar H₂ and RT. Afterfiltration the solvent is eliminated i.vac. and further purification iscarried out by column chromatography on silica gel (EtOAc/MeOH/NH₃8:2:0.2).

Yield: 3.10 g (64.2% of theory). C₁₂H₁₆N₄ (M=216.288). Calc.: molpeak(M+H)⁺: 217 Found: molpeak (M+H)⁺: 217.

3.40e 5-bromo-2-pyrrolidin-1-ylmethyl-1H-benzimidazole

3.10 g (14.3 mmol) 2-pyrrolidin-1-ylmethyl-1H-benzimidazol-5-ylamine issuspended in 32.2 mL 48% hydrobromic acid and 32.2 mL water and thesolution is cooled to 0° C. 2.5 M sodium nitrite solution (1.68 g in 9.7mL water) is slowly added dropwise, so that the internal temperaturedoes not exceed 5° C. The reaction is stirred for 10 min at 0° C. andthen 3.50 g (24.37 mmol) CuBr in 11.3 mL 48% hydrobromic acid is addeddropwise. The reaction is heated to 60° C. and stirred for one hour atthis temperature. The solvent is eliminated i.vac. and the residuetriturated with isopropanol. The precipitate is suction filtered andwashed with isopropanol. The purification is carried out by columnchromatography on silica gel (MeOH/NH₃ 9:1).

Yield: 2.20 g (54.8% of theory). C₁₂H₁₄BrN₃ (M=280.169). Calc.: molpeak(M+H)⁺: 280/282 Found: molpeak (M+H)⁺: 280/282. HPLC retention time:4.47 min (method A).

3.40f 5-iodo-2-pyrrolidin-1-ylmethyl-1H-benzimidazole

Prepared according to general working method II from5-bromo-2-pyrrolidin-1-ylmethyl-1H-benzimidazole (700 mg, 2.50 mmol).

Yield: 200 mg (24.5% of theory). C₁₂H₁₄IN₃ (M=327.170). Calc.: molpeak(M+H)⁺: 328 Found: molpeak (M+H)⁺: 328. HPLC retention time: 4.55 min(method A).

3.40g5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-pyrrolidin-1-ylmethyl-1H-benzimidazole

Prepared according to general working method I from5-iodo-2-pyrrolidin-1-ylmethyl-1H-benzimidazole (200 mg, 0.61 mmol) and5-(4-chloro-phenyl)-2-ethynyl-pyridine (131 mg, 0.61 mmol).

Yield: 5 mg (2.0% of theory). C₂₅H₂₁ClN₄ (M=412.926). Calc.: molpeak(M−H)⁻: 411/413 Found: molpeak (M−H)⁻: 411/413. HPLC retention time:3.94 min (method A).

EXAMPLE 3.415-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-1-(2-pyrrolidin-1-yl-ethyl)-1H-benzimidazole

3.41a 5-bromo-1-(2-pyrrolidin-1-yl-ethyl)-1H-benzimidazole

A solution of 904 mg (3.18 mmol)4-bromo-N¹-(2-pyrrolidin-1-yl-ethyl)-benzene-1,2-diamine in 5 mL formicacid is refluxed for 1.5 h. It is made alkaline with semisaturatedNaHCO₃ solution and extracted twice with 70 mL EtOAc. The organic phaseis dried over MgSO₄ and the solvent is eliminated i.vac.

Yield: 750 mg (80.2% of theory). C₁₃H₁₆BrN₃ (M=294.197). Calc.: molpeak(M+H)⁺: 294/296 Found: molpeak (M+H)⁺: 294/296. HPLC retention time:3.78 min (method A).

3.41b 5-iodo-1-(2-pyrrolidin-1-yl-ethyl)-1H-benzimidazole

Prepared according to general working method II from5-bromo-1-(2-pyrrolidin-1-yl-ethyl)-1H-benzimidazole (750 mg, 2.55mmol).

Yield: 680 mg (78.2% of theory). C₁₃H₁₆IN₃ (M=341.197). Calc.: molpeak(M+H)⁺: 342 Found: molpeak (M+H)⁺: 342. HPLC retention time: 4.04 min(method A).

3.41c5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-1-(2-pyrrolidin-1-yl-ethyl)-1H-benzimidazole

Prepared according to general working method I from5-iodo-1-(2-pyrrolidin-1-yl-ethyl)-1H-benzimidazole (150 mg, 0.44 mmol)and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (94 mg, 0.44 mmol).

Yield: 26 mg (13.7% of theory). C₂₆H₂₃ClN₄ (M=426.953). Calc.: molpeak(M+H)⁺: 427/429 Found: molpeak (M+H)⁺: 427/429. HPLC retention time:6.51 min (method A).

EXAMPLE 3.422-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-1-methyl-5-pyrrolidin-1-ylmethyl-1H-benzimidazole

3.42a methyl-(2-nitro-4-pyrrolidin-1-ylmethyl-phenyl)-amine

5.55 g (78.0 mmol) pyrrolidine are added to a solution of 4.70 g (26.1mmol) 4-methylamino-3-nitro-benzaldehyde in 100 mL THF and the reactionmixture is acidified with glacial acetic acid. 6.36 g (30.0 mmol)NaBH(OAc)₃ are added and the reaction mixture is stirred overnight atRT. The mixture is combined with saturated NaHCO₃ solution and theaqueous phase is extracted twice with EtOAc. The combined organicextracts are washed with 200 mL semisaturated NaHCO₃ solution and driedover MgSO₄. The solvent is eliminated i.vac. and further purification iscarried out by column chromatography on silica gel (gradient: DCM toDCM/MeOH 9:1).

Yield: 2.00 9 (32.6% of theory). C₁₂H₁₇N₃O₂ (M=235.288). Calc.: molpeak(M+H)⁺: 236 Found: molpeak (M+H)⁺: 236. R_(f) value: 0.15 (silica gel,DCM/MeOH 9:1).

3.42b N¹-methyl-4-pyrrolidin-1-ylmethyl-benzene-1,2-diamine

4.85 g (21.5 mmol) tin(II)chloride dihydrate and 4.45 g (53.0 mmol)NaHCO₃ are added to a solution of 1.00 g (4.25 mmol)methyl-(2-nitro-4-pyrrolidin-1-ylmethyl-phenyl)-amine in 60 mL EtOAc atRT. The reaction is refluxed for 2 h and then diluted with 100 mL 1 MKHSO₄ solution and some water. The mixture is filtered. The aqueousphase is combined with K₂CO₃ and extracted twice with 80 mL EtOAc. Theorganic phase is dried over MgSO₄ and the solvent is eliminated i.vac.

Yield: 850 mg (97.4% of theory). C₁₂H₁₉N₃ (M=205.305). Calc.: molpeak(M+H)⁺: 206 Found: molpeak (M+H)⁺: 206. R_(f) value: 0.15 (silica gel,DCM/MeOH/NH₃ 9:1:0.1).

3.42c 1-methyl-5-pyrrolidin-1-ylmethyl-1H-benzimidazole

A solution of 850 mg (4.14 mmol)N¹-methyl-4-pyrrolidin-1-ylmethyl-benzene-1,2-diamine in 4 mL formicacid is refluxed for 1.5 h. It is made alkaline with 250 mLsemisaturated NaHCO₃ solution and extracted twice with 70 mL EtOAc. Theorganic phase is dried over MgSO₄ and the solvent is eliminated i.vac.

Yield: 650 mg (72.9% of theory). C₁₃H₁₇N₃ (M=215.301). Calc.: molpeak(M+H)⁺: 216 Found: molpeak (M+H)⁺: 216. R_(f) value: 0.25 (silica gel,DCM/MeOH/NH₃ 9:1:0.1).

3.42d 2-iodo-1-methyl-5-pyrrolidin-1-ylmethyl-1H-benzimidazole

0.80 mL (1.28 mmol) 1.6 M n-butyllithium solution in hexane are added toa solution, cooled to −75° C., of 250 mg (1.16 mmol)1-methyl-5-pyrrolidin-1-ylmethyl-1H-benzimidazole in 8 mL THF. Thereaction mixture is stirred for 10 min at this temperature and then 288mg (1.28 mmol) N-iodosuccinimide in 5 mL THF are added. The cooling bathis removed and the reaction stirred for 1 h at RT. 12 mL 0.1 M HCl areadded and the aqueous phase is extracted with EtOAc. The organic phaseis dried over MgSO₄ and the solvent is eliminated i.vac. Thepurification is carried out by column chromatography on silica gel(gradient: DCM to DCM/MeOH/NH₃ 9:1:0.1).

Yield: 140 mg (22.2% of theory). C₁₃H₁₆IN₃ (M=341.197). Calc.: molpeak(M+H)⁺: 342 Found: molpeak (M+H)⁺: 342. R_(f) value: 0.20 (silica gel,DCM/MeOH/NH₃ 9:1:0.1). HPLC retention time: 3.89 min (method A).

3.42e2-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-1-methyl-5-pyrrolidin-1-ylmethyl-1H-benzimidazole

Prepared according to general working method I from2-iodo-1-methyl-5-pyrrolidin-1-ylmethyl-1H-benzimidazole (100 mg, 0.29mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (68 mg, 0.32 mmol).

Yield: 9 mg (7.2% of theory). C₂₆H₂₃ClN₄ (M=426.953) Calc.: molpeak(M+H)⁺: 427/429 Found: molpeak (M+H)⁺: 427/429. R_(f) value: 0.20(silica gel, DCM/MeOH/NH₃ 9:1:0.1). HPLC retention time: 6.69 min(method A).

EXAMPLE 3.435-(4-chloro-phenyl)-2-[2-fluoro-4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridine

3.43a 1-[2-(3-fluoro-4-iodo-phenoxy)-ethyl]-pyrrolidine

The product is obtained analogously to Example 3.1e from 13.6 g (57.0mmol) 3-fluoro-4-iodo-phenol and 9.69 g (57.0 mmol)N-(2-chloroethyl)-pyrrolidine hydrochloride.

Yield: 17.1 g (89.6% of theory). C₁₂H₁₅FINO (M=335.162). Calc.: molpeak(M+H)⁺: 336 Found: molpeak (M+H)⁺: 336. R_(f) value: 0.57 (silica gel,EtOAc/MeOH/NH₃ 95:5:0.5).

3.43b5-(4-chloro-phenyl)-2-[2-fluoro-4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridine

Prepared according to general working method I from1-[2-(3-fluoro-4-iodo-phenoxy)-ethyl]-pyrrolidine (500 mg, 0.75 mmol)and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (159 mg, 0.75 mmol).

Yield: 48 mg (15.4% of theory). C₂₅H₂₂ClFN₂O (M=420.918). Calc.: molpeak(M+H)⁺: 421/423 Found: molpeak (M+H)⁺: 421/423. R_(f) value: 0.65(silica gel, EtOAc/MeOH/NH₃ 9:1:0.1). HPLC retention time: 7.74 min(method A).

EXAMPLE 3.445-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-8-(2-pyrrolidin-1-yl-ethoxy)-quinoline

3.44a 5-iodo-8-(2-pyrrolidin-1-yl-ethoxy)-quinoline

The product is obtained analogously to Example 3.1e from 700 mg (2.58mmol) 5-iodo-quinolin-8-ol and 450 mg (2.59 mmol)N-(2-chloroethyl)-pyrrolidine hydrochloride.

Yield: 829 mg (87.2% of theory). C₁₅H₁₇IN₂O (M=368.220). Calc.: molpeak(M+H)⁺: 369 Found: molpeak (M+H)⁺: 369. HPLC retention time: 5.56 min(method B).

3.44b5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-8-(2-pyrrolidin-1-yl-ethoxy)-quinoline

Prepared according to general working method I from5-iodo-8-(2-pyrrolidin-1-yl-ethoxy)-quinoline (200 mg, 0.54 mmol) and5-(4-chloro-phenyl)-2-ethynyl-pyridine (116 mg, 0.54 mmol).

Yield: 23 mg (9.4% of theory). C₂₈H₂₄ClN₃O (M=453.976). Calc.: molpeak(M+H)⁺: 454/456 Found: molpeak (M+H)⁺: 454/456. HPLC retention time:7.40 min (method A).

EXAMPLE 3.456-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-pyrrolidin-1-ylmethyl-quinoline

3.45a 6-bromo-2-bromomethyl-quinoline

148 mg (1.00 mmol) α,α-azoisobutyronitrile and 8.01 g (45.0 mmol)N-bromosuccinimide are added successively to a solution of 10.0 g (45.0mmol) 6-bromo-2-methyl-quinoline in 60 mL carbon tetrachloride. Thereaction mixture is refluxed for 8 h. It is filtered and the filtrate iswashed twice with water. The organic phase is dried over MgSO₄ and thesolvent is eliminated i.vac. The purification is carried out by columnchromatography on silica gel (PE/EtOAc 4:1).

Yield: 5.10 g (37.7% of theory). C₁₀H₇Br₂N (M=300.982). Calc.: molpeak(M+H)⁺: 300/302/304 Found: molpeak (M+H)⁺: 300/302/304. HPLC retentiontime: 5.75 min (method B).

3.45b 6-bromo-2-pyrrolidin-1-ylmethyl-quinoline

4.60 g (15.28 mmol) 6-bromo-2-bromomethyl-quinoline are added to asolution of 1.40 mL (16.8 mmol) pyrrolidine and 6.34 g (45.9 mmol) K₂CO₃in 50 mL acetonitrile. The reaction is stirred overnight at RT and thenthe inorganic salts are filtered off. The organic phase is washed withwater and the aqueous phase is extracted with EtOAc. The combinedorganic extracts are dried over MgSO₄ and the solvent is eliminatedi.vac.

Yield: 4.45 g (100% of theory). C₁₄H₁₅BrN₂ (M=291.193). Calc.: molpeak(M+H)⁺: 291/293 Found: molpeak (M+H)⁺: 291/293. R_(f) value: 0.27(silica gel, DCM/MeOH 9:1).

3.45c 6-iodo-2-pyrrolidin-1-ylmethyl-quinoline

Prepared according to general working method II from6-bromo-2-pyrrolidin-1-ylmethyl-quinoline (500 mg, 1.72 mmol).

Yield: 400 mg (59.9% of theory). C₁₄H₁₅IN₂ (M=338.193). Calc.: molpeak(M+H)⁺: 339 Found: molpeak (M+H)⁺: 339. HPLC retention time: 5.16 min(method A).

3.45d6-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-pyrrolidin-1-ylmethyl-quinoline

Prepared according to general working method I from6-iodo-2-pyrrolidin-1-ylmethyl-quinoline (151 mg, 0.45 mmol) and5-(4-chloro-phenyl)-2-ethynyl-pyridine (80 mg, 0.37 mmol).

Yield: 18 mg (11.4% of theory). C₂₇H₂₂ClN₃ (M=423.949). Calc.: molpeak(M+H)⁺: 424/426 Found: molpeak (M+H)⁺: 424/426. HPLC retention time:4.78 min (method B).

EXAMPLE 3.466-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-pyrrolidin-1-ylmethyl-1,2,3,4-tetrahydro-quinoline

3.46a 6-bromo-2-pyrrolidin-1-ylmethyl-1,2,3,4-tetrahydro-quinoline

Under an argon atmosphere 0.69 mL (6.87 mmol) borane-pyridine complexare added to a solution of 500 mg (1.72 mmol)6-bromo-2-pyrrolidin-1-ylmethyl-quinoline (see 3.45b) in 10 mL aceticacid at RT. The mixture is stirred for 7 h at RT, again combined with0.35 mL (3.46 mmol) borane-pyridine complex and stirred for another hourat RT. It is cooled to 0° C. and the solution is made basic with 8% NaOHsolution. The aqueous phase is extracted with EtOAc and the solvent iseliminated i.vac. The residue is taken up with water and acidified with12% HCl. The aqueous phase is extracted with EtOAc and then made basicwith 20% NaOH solution while cooling with ice. The aqueous phase isextracted with EtOAc. The organic phase is dried over MgSO₄ and thesolvent is eliminated i.vac.

Yield: 420 mg (82.9% of theory). C₁₄H₁₉BrN₂ (M=295.25). Calc.: molpeak(M+H)⁺: 295/297 Found: molpeak (M+H)⁺: 295/297. HPLC retention time:5.01 min (method B).

3.46b 6-iodo-2-pyrrolidin-1-ylmethyl-1,2,3,4-tetrahydro-quinoline

Prepared according to general working method II from6-bromo-2-pyrrolidin-1-ylmethyl-1,2,3,4-tetrahydro-quinoline (280 mg,0.95 mmol).

Yield: 260 mg (80.1% of theory). C₁₄H₁₉IN₂ (M=342.225). Calc.: molpeak(M+H)⁺: 343 Found: molpeak (M+H)⁺: 343. HPLC retention time: 5.34 min(method A).

3.46c6-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-pyrrolidin-1-ylmethyl-1,2,3,4-tetrahydro-quinoline

Prepared according to general working method I from6-iodo-2-pyrrolidin-1-ylmethyl-1,2,3,4-tetrahydro-quinoline (260 mg,0.76 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (162 mg, 0.76mmol).

Yield: 72 mg (22.1% of theory). C₂₇H₂₆ClN₃ (M=427.981). Calc.: molpeak(M+H)⁺: 428 Found: molpeak (M+H)⁺: 428. HPLC retention time: 4.66 min(method B).

EXAMPLE 3.475-(4-chloro-phenyl)-2-(6-pyrrolidin-1-ylmethyl-naphthalen-2-ylethynyl)-pyridine

3.47a (6-iodo-naphthalen-2-yl)-methanol

Prepared according to general working method II from(6-bromo-naphthalen-2-yl)-methanol (500 mg, 2.11 mmol).

Yield: 450 mg (75.1% of theory). C₁₁H₉IO (M=284.10). Calc.: molpeak(M+H)⁺: 284 Found: molpeak (M+H)⁺: 284. HPLC retention time: 8.30 min(method A).

3.47b{6-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-naphthalen-2-yl}-methanol

Prepared according to general working method I from(6-iodo-naphthalen-2-yl)-methanol (450 mg, 1.58 mmol) and5-(4-chloro-phenyl)-2-ethynyl-pyridine (342 mg, 1.60 mmol).

Yield: 250 mg (42.8% of theory). C₂₄H₁₆ClNO (M=369.85). Calc.: molpeak(M+H)⁺: 370/372 Found: molpeak (M+H)⁺: 370/372. R_(f) value: 0.25(silica gel, DCM/MeOH 19:1).

3.47c5-(4-chloro-phenyl)-2-(6-pyrrolidin-1-ylmethyl-naphthalen-2-ylethynyl)-pyridine

58 μL (0.80 mmol) thionyl chloride are added at 0° C. to a solution of148 mg (0.40 mmol){6-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-naphthalen-2-yl}-methanolin 5 mL DCM. The solution is heated to RT and stirred for 1 h at thistemperature. The reaction mixture is diluted with 30 mL DCM, combinedwith ice water, made alkaline with saturated NaHCO₃ solution and theorganic phase is washed with water. The organic phase is dried overMgSO₄ and filtered. 0.10 mL (1.20 mmol) pyrrolidine are added to thefiltrate, which is stirred for 2 h at RT and for 1 h at 40° C. Thesolvent is eliminated i.vac. and the purification is carried out bycolumn chromatography on silica gel (gradient: DCM to DCM/MeOH/NH₃5:1:0.1).

Yield: 40 mg (23.6% of theory). C₂₈H₂₃ClN₂ (M=422.96). Calc.: molpeak(M+H)⁺: 423/425 Found: molpeak (M+H)⁺: 423/425. R_(f) value: 0.10(silica gel, DCM/MeOH/NH₃ 19:1:0.1).

EXAMPLE 3.485-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-1-(2-pyrrolidin-1-yl-ethyl)-2,3-dihydro-1H-indole

3.48a 5-bromo-1-(2-pyrrolidin-1-yl-ethyl)-2,3-dihydro-1H-indole

Under a nitrogen atmosphere 700 mg (3.46 mmol) 5-bromoindoline are addedto a solution of 722 mg (4.16 mmol) N-(2-chloroethyl)-pyrrolidinehydrochloride and 1.19 mL (6.93 mmol) ethyldiisopropylamine in 10 mLDMF. The reaction solution is stirred for 21 h at RT and again combinedwith N-(2-chloroethyl)-pyrrolidine hydrochloride. The reaction solutionis heated to 70° C. and stirred for 4 h at this temperature. The solventis eliminated i.vac. and the residue taken up in 50 mL semisaturatedNaCl solution and 50 mL EtOAc. The aqueous phase is extracted twice with50 mL DCM, the combined organic extracts are dried over Na₂SO₄ and thesolvent is eliminated i.vac.

Yield: 226 mg (22.1% of theory). C₁₄H₁₉BrN₂ (M=295.225). Calc.: molpeak(M+H)⁺: 295/297 Found: molpeak (M+H)⁺: 295/297. HPLC retention time:5.93 min (method A).

3.48b 5-iodo-1-(2-pyrrolidin-1-yl-ethyl)-2,3-dihydro-1H-indole

Prepared according to general working method II from5-bromo-1-(2-pyrrolidin-1-yl-ethyl)-2,3-dihydro-1H-indole (226 mg, 0.77mmol).

Yield: 142 mg (54.2% of theory). C₁₄H₁₉IN₂ (M=342.225). HPLC retentiontime: 6.10 min (method A).

3.48c5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-1-(2-pyrrolidin-1-yl-ethyl)-2,3-dihydro-1H-indole

Prepared according to general working method I from5-iodo-1-(2-pyrrolidin-1-yl-ethyl)-2,3-dihydro-1H-indole (142 mg, 0.42mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (89 mg, 0.42 mmol).

Yield: 39 mg (22.1% of theory). C₂₇H₂₆ClN₃ (M=427.981). Calc.: molpeak(M+H)⁺: 428/430 Found: molpeak (M+H)⁺: 428/430. R_(f) value: 0.55 (Alox,cyc/EtOAc 2:1). HPLC retention time: 7.98 min (method A).

EXAMPLE 3.495-(4-chloro-phenyl)-2-[4-(1-methyl-2-piperidin-1-yl-ethoxy)-phenylethynyl]-pyridine

3.49a 1-[2-(4-iodo-phenoxy)-propyl]-piperidine

1.54 g (7.00 mmol) iodobenzene and 2.75 g (10.5 mmol) triphenylphosphaneare added successively to a solution of 1.00 g (6.98 mmol)1-piperidin-1-yl-propan-2-ol in 20 mL DCM. 2.19 mL (10.5 mmol, 95%)diisopropyl azodicarboxylate is added dropwise at RT and the reaction isstirred for 2 h at RT. It is diluted with water, the organic phase iswashed with water and dried over MgSO₄. After the desiccant and solventhave been eliminated the residue is purified by chromatography (silicagel, DCM/MeOH 9:1). The oily residue is triturated withdiisopropylether, filtered off from the insoluble residue and thefiltrate is evaporated to dryness i.vac.

Yield: 500 mg (20.7% of theory). C₁₄H₂₀INO (M=345.226). Calc.: molpeak(M+H)⁺: 346 Found: molpeak (M+H)⁺: 346. R_(f) value: 0.32 (silica gel,DCM/MeOH 9:1).

3.49b5-(4-chloro-phenyl)-2-[4-(1-methyl-2-piperidin-1-yl-ethoxy)-phenylethynyl]-pyridine

Prepared according to general working method I from1-[2-(4-iodo-phenoxy)-propyl]-piperidine (173 mg, 0.50 mmol) and5-(4-chloro-phenyl)-2-ethynyl-pyridine (107 mg, 0.50 mmol).

Yield: 80 mg (37.1% of theory). C₂₇H₂₇ClN₂O (M=430.982). Calc.: molpeak(M+H)⁺: 431/433 Found: molpeak (M+H)⁺: 431/433. R_(f) value: 0.25(silica gel, EtOAc/MeOH 9:1). HPLC retention time: 5.03 min (method A).

EXAMPLE 3.505-(4-chloro-phenyl)-2-[4-(3-piperidin-1-yl-pyrrolidin-1-yl)-phenylethynyl]-pyridine

3.50a 1-(1-benzyl-pyrrolidin-3-yl)-piperidine

12.7 g (60.0 mmol) NaBH(OAc)₃ and 2.3 mL acetic acid are added to asolution of 4.94 mL (50.0 mmol) piperidine and 8.03 mL (50.0 mmol)N-benzylpyrrolidinone in 200 mL THF. The reaction is stirred overnightat RT. The reaction solution is combined with 200 mL saturated NaHCO₃solution and extracted twice with 200 mL EtOAc. The organic phase isdried over MgSO₄ and the solvent is eliminated i.vac. The purificationis carried out by column chromatography on silica gel (EtOAc/MeOH/NH₃8:2:0.2).

Yield: 5.50 g (45.0% of theory). C₁₆H₂₄N₂ (M=244.383). Calc.: molpeak(M+H)⁺: 245 Found: molpeak (M+H)⁺: 245. R_(f) value: 0.25 (silica gel,EtOAc/MeOH/NH₃ 9:1:0.1).

3.50b 1-pyrrolidin-3-yl-piperidine

550 mg 10% Pd/C are added to a solution of 5.50 g (22.5 mmol)1-(1-benzyl-pyrrolidin-3-yl)-piperidine in 200 mL MeOH. The reactionsolution is stirred for 5 h at RT and 3 bar H₂. 550 mgpalladiumhydroxide are added and the reaction is stirred for a further 6h at RT and 3 bar H₂. The catalyst is suction filtered and the solventis eliminated i.vac.

Yield: 900 mg (86.5% of theory). C₉H₁₈N₂ (M=154.257). Calc.: molpeak(M+H)⁺: 155 Found: molpeak (M+H)⁺: 155. R_(f) value: 0.05 (silica gel,EtOAc/MeOH/NH₃ 8:2:0.2).

3.50c 1-[1-(4-bromo-phenyl)-pyrrolidin-3-yl]-piperidin

283 mg (1.00 mmol) 4-bromo-iodobenzene, 10 mg (0.05 mmol) CuI, 124 mg(2.00 mmol) ethyleneglycol and 424 mg (2.00 mmol) potassium phosphateare added to a reaction vessel, which is evacuated and rinsed with argonseveral times. Then 154 mg (1.00 mmol) 1-pyrrolidin-3-yl-piperidine in 1mL isopropanol are added and the reaction is shaken for 15 h at 80° C.The reaction solution is diluted with EtOAc and extracted twice with 5%ammonia solution. The organic phase is dried over MgSO₄ and the solventis eliminated i.vac.

Yield: 230 mg (74.4% of theory). C₁₅H₂₁BrN₂ (M=309.252). Calc.: molpeak(M+H)⁺: 309/311 Found: molpeak (M+H)⁺: 309/311. R_(f) value: 0.73(silica gel, DCM/MeOH/NH₃ 9:1:0.1).

3.50d 1-[1-(4-iodo-phenyl)-pyrrolidin-3-yl]-piperidine

Prepared according to general working method II from1-[1-(4-bromo-phenyl)-pyrrolidin-3-yl]-piperidine (200 mg, 0.65 mmol).

Yield: 120 mg (52.1% of theory). C₁₅H₂₁IN₂ (M=356.252). Calc.: molpeak(M+H)⁺: 357 Found: molpeak (M+H)⁺: 357. HPLC retention time: 6.13 min(method A).

3.50e5-(4-chloro-phenyl)-2-[4-(3-piperidin-1-yl-pyrrolidin-1-yl)-phenylethynyl]-pyridine

Prepared according to general working method I from1-[1-(4-iodo-phenyl)-pyrrolidin-3-yl]-piperidine (120 mg, 0.34 mmol) and5-(4-chloro-phenyl)-2-ethynyl-pyridine (73 mg, 0.34 mmol).

Yield: 75 mg (50.4% of theory). C₂₈H₂₈ClN₃ (M=442.008). Calc.: molpeak(M+H)⁺: 442/444 Found: molpeak (M+H)⁺: 442/444. R_(f) value: 0.30(silica gel, DCM/MeOH/NH₃ 9:1:0.1). HPLC retention time: 4.94 min(method B).

EXAMPLE 3.515-(4-chloro-phenyl)-2-[5-(2-pyrrolidin-1-yl-ethoxy)-pyridin-2-yl-ethynyl]-pyridine

3.51a 2-bromo-5-(2-pyrrolidin-1-yl-ethoxy)-pyridine

The product is obtained analogously to Example 3.1e (1:1 mixture ofacetone:acetonitrile instead of DMF) from 3.90 g (22.4 mmol)6-bromo-pyridin-3-ol and 4.25 g (25.0 mmol)N-(2-chloroethyl)-pyrrolidine hydrochloride.

Yield: 4.70 g (69.3% of theory). C₁₁H₁₅BrN₂O (M=271.159). Calc.: molpeak(M+H)⁺: 271/273 Found: molpeak (M+H)⁺: 271/273. R_(f) value: 0.27(silica gel, EtOAc/MeOH/NH₃ 9:1:0.1).

3.51b5-(4-chloro-phenyl)-2-[5-(2-pyrrolidin-1-yl-ethoxy)-pyridin-2-yl-ethynyl]-pyridine

Prepared according to general working method I from2-bromo-5-(2-pyrrolidin-1-yl-ethoxy)-pyridine (271 mg, 0.50 mmol) and5-(4-chloro-phenyl)-2-ethynyl-pyridine (106 mg, 0.50 mmol).

Yield: 22 mg (10.9% of theory). C₂₄H₂₂ClN₃O (M=403.915). Calc.: molpeak(M+H)⁺: 404/406 Found: molpeak (M+H)⁺: 404/406. R_(f) value: 0.20(silica gel, EtOAc/MeOH/NH₃ 9:1:0.1).

EXAMPLE 3.525-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-(2-pyrrolidin-1-yl-ethoxy)-benzonitrile

3.52a 5-bromo-2-(2-pyrrolidin-1-yl-ethoxy)-benzonitrile

The product is obtained analogously to Example 3.1e (acetonitrileinstead of DMF) from 2.00 g (10.1 mmol) 5-bromo-2-hydroxy-benzonitrileand 2.00 g (11.8 mmol) N-(2-chloroethyl)-pyrrolidine hydrochloride.

Yield: 1.32 g (44.3% of theory). C₁₃H₁₅BrN₂O (M=295.181). Calc.: molpeak(M+H)⁺: 295/297 Found: molpeak (M+H)⁺: 295/297. HPLC retention time:4.91 min (method A).

3.52b 5-iodo-2-(2-pyrrolidin-1-yl-ethoxy)-benzonitrile

Prepared according to general working method II from5-bromo-2-(2-pyrrolidin-1-yl-ethoxy)-benzonitrile (350 mg, 1.19 mmol).

Yield: 324 mg (79.8% of theory). C₁₃H₁₅IN₂O (M=342.182). Calc.: molpeak(M+H)⁺: 343 Found: molpeak (M+H)⁺: 343. HPLC retention time: 5.14 min(method A).

3.52c5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-(2-pyrrolidin-1-yl-ethoxy)-benzonitrile

Prepared according to general working method I from5-iodo-2-(2-pyrrolidin-1-yl-ethoxy)-benzonitrile (300 mg, 0.88 mmol) and5-(4-chloro-phenyl)-2-ethynyl-pyridine (206 mg, 0.97 mmol).

Yield: 76 mg (20.3% of theory). C₂₆H₂₂ClN₃O (M=427.938). Calc.: molpeak(M+H)⁺: 428/430 Found: molpeak (M+H)⁺: 428/430. HPLC retention time:7.31 min (method A).

EXAMPLE 3.535-(4-chloro-phenyl)-2-[2-(4-methyl-piperidin-1-ylmethyl)-benzofuran-5-ylethynyl]-pyridine

3.53a ethyl 5-bromo-benzofuran-2-carboxylate

13.8 g (100 mmol) Na₂CO₃ are added to a solution of 4.02 g (20.0 mmol)5-bromo-salicylaldehyde and 2.26 mL (20.0 mmol, 98%) ethyl bromoacetatein 50 mL DMF. The reaction mixture is heated to 80° C. and stirred for 2h at this temperature. It is diluted with 200 mL water, the aqueousphase is extracted three times with 100 mL tert-butylmethylether and thecombined organic extracts are washed twice with 50 mL water. The organicphase is dried over MgSO₄, filtered through activated charcoal and thesolvent is eliminated i.vac.

Yield: 3.80 g (70.6% of theory). C₁₁H₉BrO₃ (M=269.097). Calc.: molpeak(M+H)⁺: 269/271 Found: molpeak (M+H)⁺: 269/271. R_(f) value: 0.75(silica gel, PE/EtOAc 8:2).

3.53b (5-bromo-benzofuran-2-yl)-methanol

7.0 mL (7.00 mmol) 1 M lithium aluminium hydride solution in THF isslowly added dropwise at −5° C. to a solution of 3.70 g (13.8 mmol)ethyl 5-bromo-benzofuran-2-carboxylate in 50 mL THF. The reactionsolution is heated to RT and then cooled again to 10° C. Another 0.7 mL(0.70 mmol) 1 M lithium aluminium hydride solution in THF areadded-dropwise and the reaction is stirred for 1 h at RT. 1.0 mL water,1.0 mL 15% NaOH and finally 3.0 mL water are added successively to thereaction mixture and the insoluble precipitate is filtered off. Theorganic phase is dried over MgSO₄, filtered through activated charcoaland the solvent is eliminated i.vac.

Yield: 2.10 g (67.3% of theory). C₉H₇BrO₂ (M=227.059). Calc.: molpeak(M)⁺: 226/228 Found: molpeak (M)⁺: 226/228. R_(f) value: 0.15 (silicagel, PE/EtOAc 8:2).

3.53c (5-iodo-benzofuran-2-yl)-methanol

Prepared according to general working method II from(5-bromo-benzofuran-2-yl)-methanol (2.10 g, 9.25 mmol).

Yield: 2.53 g (100% of theory). C₉H₇IO₂ (M=274.059). Calc.: molpeak(M)⁺: 274 Found: molpeak (M)⁺: 274. R_(f) value: 0.26 (silica gel,PE/EtOAc 8:2).

3.53d{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-benzofuran-2-yl}-methanol

Prepared according to general working method I from(5-iodo-benzofuran-2-yl)-methanol (685 mg, 2.50 mmol) and5-(4-chloro-phenyl)-2-ethynyl-pyridine (534 mg, 2.50 mmol).

Yield: 400 mg (44.5% of theory). C₂₂H₁₄ClNO₂ (M=359.815). Calc.: molpeak(M+H)⁺: 360/362 Found: molpeak (M+H)⁺: 360/362. R_(f) value: 0.58(silica gel, DCM/MeOH/NH₃ 9:1:0.1).

3.53e5-(4-chloro-phenyl)-2-[2-(4-methyl-piperidin-1-ylmethyl)-benzofuran-5-ylethynyl]-pyridine

32 μL (0.40 mmol) methanesulphonic acid chloride are added to a solutionof 100 mg (0.28 mmol){5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-benzofuran-2-yl}-methanoland 69 μL (0.50 mmol) triethylamine in 5 mL DCM at 0° C. and thereaction is stirred for 1 h at this temperature. Another 70 μL (0.89mmol) methanesulphonic acid chloride are added and the reaction isstirred overnight at RT. Then 0.24 ml (2.00 mmol) 4-methylpiperidine isadded and the reaction is stirred for 2 hours at RT. The reactionsolution is diluted with water and the aqueous phase extracted twicewith DCM. The organic phase is dried over MgSO₄ and the solvent iseliminated i.vac. The purification is carried out by columnchromatography on silica gel (DCM/methanol 9:1).

Yield: 10 mg (8.1% of theory). C₂₈H₂₅ClN₂O (M=440.977). Calc.: molpeak(M+H)⁺: 441/443 Found: molpeak (M+H)⁺: 441/443. R_(f) value: 0.27(silica gel, DCM/MeOH 9:1).

EXAMPLE 3.54{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-(2-pyrrolidin-1-yl-ethyl)-amine

3.54a 2-chloro-N-(4-iodo-phenyl)-acetamide

2.0 mL (25.1 mmol) chloro-acetylchloride in 5 mL DCM are added to asolution of 5.00 g (22.83 mmol) 4-iodo-phenylamine and 7.0 mL (50.2mmol) triethylamine in 100 mL DCM at 0° C. The ice bath is removed andthe reaction is stirred for a further 1.5 h at RT. The reaction solutionis diluted with 80 mL water and the organic phase is washed withsaturated NaCl solution. The organic phase is dried over MgSO₄ and thesolvent is eliminated i.vac. The residue is triturated with EtOAc,suction filtered and dried in the air.

Yield: 2.25 g (33.4% of theory). C₈H₇ClINO (M=295.508). Calc.: molpeak(M+H)⁺: 296/298 Found: molpeak (M+H)⁺: 296/298. HPLC retention time:7.91 min (method A).

3.54b N-(4-iodo-phenyl)-2-pyrrolidin-1-yl-acetamide

1.53 mL (18.6 mmol) pyrrolidine are added to a solution of 2.20 g (7.45mmol) 2-chloro-N-(4-iodo-phenyl)-acetamide in 50 mL DCM. The reactionsolution is stirred overnight at RT. The mixture is filtered, thefiltrate dried over MgSO₄ and the solvent is eliminated i.vac.

Yield: 1.65 g (67.1% of theory). C₁₂H₁₅IN₂O (M=330.171). Calc.: molpeak(M+H)⁺: 331 Found: molpeak (M+H)⁺: 331. HPLC retention time: 5.10 min(method A).

3.54c (4-iodo-phenyl)-(2-pyrrolidin-1-yl-ethyl)-amine

2.25 mL (2.25 mmol) 1 M lithium aluminium hydride solution are added toa solution of 500 mg (1.51 mmol)N-(4-iodo-phenyl)-2-pyrrolidin-1-yl-acetamide in 10 mL THF at 0° C. andthe reaction is stirred for 20 min at this temperature. EtOAc is addedand then 85 μL water, 85 μL 15% NaOH solution and finally 256 μL waterare added. The precipitate is removed by suction filtering and thefiltrate is diluted with 50 mL EtOAc. The organic phase is washed with30 mL saturated NaHCO₃ solution. The organic phase is dried over MgSO₄and the solvent is eliminated i.vac.

Yield: 450 mg (94.0% of theory). C₁₂H₁₇IN₂ (M=316.187). Calc.: molpeak(M+H)⁺: 317 Found: molpeak (M+H)⁺: 317. R_(f) value: 0.17 (silica gel,DCM/MeOH/NH₃ 9:1:0.1).

3.54d{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-(2-pyrrolidin-1-yl-ethyl)-amine

Prepared according to general working method I from(4-iodo-phenyl)-(2-pyrrolidin-1-yl-ethyl)-amine (450 mg, 1.42 mmol) and5-(4-chloro-phenyl)-2-ethynyl-pyridine (450 mg, 2.11 mmol).

Yield: 98 mg (17.1% of theory). C₂₅H₂₄ClN₃ (M=401.943). Calc.: molpeak(M+H)⁺: 402/404 Found: molpeak (M+H)⁺: 402/404. HPLC retention time:7.08 min (method A).

EXAMPLE 3.555-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-(2-pyrrolidin-1-yl-ethoxy)-benzaldehyde

3.55a 5-iodo-2-(2-pyrrolidin-1-yl-ethoxy)-benzaldehyde

The product is obtained analogously to Example 3.1e (acetonitrileinstead of DMF) from 8.93 g (36.0 mmol) 2-hydroxy-5-iodo-benzaldehydeand 7.14 g (42.0 mmol) N-(2-chloroethyl)-pyrrolidine hydrochloride.

Yield: 4.80 g (38.6% of theory). C₁₃H₁₆INO₂ (M=345.182). Calc.: molpeak(M+H)⁺: 346 Found: molpeak (M+H)⁺: 346. HPLC retention time: 5.27 min(method A).

3.55b5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-(2-pyrrolidin-1-yl-ethoxy)-benzaldehyde

Prepared according to general working method I from5-iodo-2-(2-pyrrolidin-1-yl-ethoxy)-benzaldehyde (1.50 g, 4.35 mmol) and5-(4-chloro-phenyl)-2-ethynyl-pyridine (214 mg, 5.00 mmol).

Yield: 320 mg (17.1% of theory). C₂₆H₂₃ClN₂O₂ (M=430.938). Calc.:molpeak (M+H)⁺: 431/433 Found: molpeak (M+H)⁺: 431/433. HPLC retentiontime: 7.31 min (method A).

EXAMPLE 3.565-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-(2-pyrrolidin-1-yl-ethoxy)-benzaldehyde-oxime

27 mg (0.38 mmol) hydroxylamine and 53 μL (0.38 mmol) triethylamine areadded to a solution of 200 mg (0.35 mmol)5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-(2-pyrrolidin-1-yl-ethoxy)-benzaldehyde(Example 3.55b) in 2 mL of a 1:1 mixture of acetonitrile and MeOH. Thereaction solution is heated to 85° C. After the reaction is complete themixture is diluted with water and saturated NaHCO₃ solution and theorganic phase is extracted with DCM. The organic phase is dried overMgSO₄ and the solvent is eliminated i.vac. The purification is carriedout by column chromatography using HPLC-MS.

Yield: 5 mg (3.2% of theory). C₂₆H₂₄ClN₃O₂ (M=445.953). Calc.: molpeak(M+H)⁺: 446/448 Found: molpeak (M+H)⁺: 446/448. HPLC retention time:5.25 min (method A).

EXAMPLE 3.575-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-(2-pyrrolidin-1-yl-ethoxy)-benzaldehydeO-methyl-oxime

The product is obtained analogously to Example 3.56a from 250 mg (0.44mmol)5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-(2-pyrrolidin-1-yl-ethoxy)-benzaldehyde(Example 3.55b) and 50 mg (0.60 mmol) O-methyl-hydroxylamine.

Yield: 40 mg (20.1% of theory). C₂₇H₂₆ClN₃O₂ (M=459.980). Calc.: molpeak(M+H)⁺: 460/462 Found: molpeak (M+H)⁺: 460/462. HPLC retention time:8.11 min (method A).

EXAMPLE 3.585-(4-chloro-phenyl)-2-[3-ethynyl-4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridine

152 mg (0.79 mmol) dimethyl (1-diazo-2-oxo-propyl)-phosphate in 2 mLMeOH are added to a solution of 300 mg (0.66 mmol)5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-(2-pyrrolidin-1-yl-ethoxy)-benzaldehyde(Example 3.55b) and 183 mg (1.32 mmol) K₂CO₃ in 9 mL MeOH. The reactionsolution is stirred for for 3 h at RT and diluted with 20 mL DCM. Theorganic phase is extracted twice with saturated NaHCO₃ solution. Theorganic phase is dried over MgSO₄ and the solvent is eliminated i.vac.The purification is carried out by HPLC-MS.

Yield: 104 mg (37.0% of theory). C₂₇H₂₃ClN₂O (M=426.950). Calc.: molpeak(M+H)⁺: 427/429 Found: molpeak (M+H)⁺: 427/429. HPLC retention time:7.69 min (method A).

EXAMPLE 3.59 2-pyrrolidin-1-yl-ethyl5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2,3-dihydro-indole-1-carboxylate

3.59a 2-pyrrolidin-1-yl-ethyl 5-bromo-2,3-dihydro-indole-1-carboxylate

1.00 g (4.95 mmol) 5-bromoindoline is added to a solution of 868 mg(5.00 mmol) N-(2-chloroethyl)-pyrrolidine hydrochloride and 1.70 g (12.2mmol) K₂CO₃ in 15 mL DMF. The reaction solution is stirred for 4 h at70° C. and more N-(2-chloroethyl)-pyrrolidine hydrochloride is added.The reaction solution is stirred for a further 3 h at 70° C. and thendiluted with 25 mL water. The aqueous phase is extracted twice with 30mL EtOAc. The organic phase is washed with saturated NaCl solution,dried over Na₂SO₄ and the solvent is eliminated i.vac. The purificationis carried out by column chromatography on silica gel (gradient:EtOAc/MeOH 9:1 to EtOAc/MeOH 4:1).

Yield: 687 mg (47.0% of theory). C₁₅H₁₉BrN₂O₂ (M=339.235). Calc.:molpeak (M+H)⁺: 339/341 Found: molpeak (M+H)⁺: 339/341. R_(f) value:0.62 (silica gel, EtOAc/MeOH/NH₃ 9:1:0.1).

3.59b 2-pyrrolidin-1-yl-ethyl 5-iodo-2,3-dihydro-indole-1-carboxylate

Prepared according to general working method II from2-pyrrolidin-1-yl-ethyl 5-bromo-2,3-dihydro-indole-1-carboxylate (700mg, 2.37 mmol).

Yield: 590 mg (64.4% of theory). C₁₅H₁₉IN₂O₂ (M=386.235). Calc.: molpeak(M+H)⁺: 387 Found: molpeak (M+H)⁺: 387. R_(f) value: 0.37 (silica gel,EtOAc/MeOH/NH₃ 9:1:0.1).

3.59c 2-pyrrolidin-1-yl-ethyl5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2,3-dihydro-indole-1-carboxylate

Prepared according to general working method I from2-pyrrolidin-1-yl-ethyl 5-iodo-2,3-dihydro-indole-1-carboxylate (120 mg,0.31 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (80 mg, 0.37mmol).

Yield: 48 mg (32.8% of theory). C₂₈H₂₆ClN₃O₂ (M=471.991). Calc.: molpeak(M+H)⁺: 472/474 Found: molpeak (M+H)⁺: 472/474. HPLC retention time:7.66 min (method A).

EXAMPLE 3.603-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-6,7,8,9-tetrahydro-5H-10-thia-7-aza-benzo[a]azulene

3.60a ethyl 4-bromo-5-oxo-azepan-1-carboxylate

79.9 g (500 mmol) bromine are added to a solution of 92.7 g (500 mmol)ethyl 4-oxo-azepan-1-carboxylate in 350 mL chloroform and the reactionis stirred overnight. The reaction solution is washed three times withsaturated NaHCO₃ solution, the organic phase is dried over Na₂SO₄ andthe solvent is eliminated i.vac. The product is further reacted withoutpurification.

Yield: 118 g (89.3% of theory). C₉H₁₄BrNO₃ (M=264.135).

3.60b ethyl 4-(4-bromo-phenylsulphanyl)-5-oxo-azepan-1-carboxylate

60.5 g (320 mmol) 4-bromothiophenol in 300 mL chloroform are added to asolution of 84.5 g (320 mmol) ethyl 4-bromo-5-oxo-azepan-1-carboxylateand 32.4 g (320 mmol) triethylamine in 80 mL chloroform over 45 min, sothat the internal temperature does not exceed 40° C. The reactionsolution is stirred for 1.5 h at RT. The reaction mixture is washedtwice with dilute ammonia solution and twice with water. The organicphase is dried over Na₂SO₄ and K₂CO₃ and the solvent is eliminatedi.vac. The purification is carried out by repeated column chromatographyon silica gel.

Yield: 44.4 g (37.2% of theory). C₁₅H₁₈BrNO₃S (M=372.30). R_(f) value:0.33 (silica gel, chloroform/acetone 19:1).

3.60c ethyl3-bromo-5,6,8,9-tetrahydro-10-thia-7-aza-benzo[a]azulen-7-carboxylate

A solution of 44.3 g (119 mmol) ethyl4-(4-bromo-phenylsulphanyl)-5-oxo-azepan-1-carboxylate in 443 gpolyphosphoric acid is heated to 80° C. for 45 min and then diluted with1000 mL water. The aqueous phase is extracted three times withchloroform. The organic phase is washed with water, dried over Na₂SO₄and the solvent is eliminated i.vac. The purification is carried out byrepeated column chromatography on silica gel (chloroform/EtOAc 19:1) andby recrystallisation from MeOH/acetone.

Yield: 22.4 g (52.8% of theory). C₁₅H₁₆BrNO₂S (M=354.28). melting point:109° C.

3.60d 3-bromo-6,7,8,9-tetrahydro-5H-10-thia-7-aza-benzo[a]azulene

30.0 g (53.5 mmol) KOH in 700 mL EtOH are added to a solution of 19.0 g(53.5 mmol) ethyl3-bromo-5,6,8,9-tetrahydro-10-thia-7-aza-benzo[a]azulen-7-carboxylate.EtOH is distilled off at normal pressure and the residue is taken up inwater. The solution is acidified with HCl. Then it is made basic withNaOH and the aqueous phase is extracted four times with chloroform. Theorganic phase is dried over Na₂SO₄ and K₂CO₃ and the solvent iseliminated i.vac. The purification is carried out by repeated columnchromatography on silica gel.

Yield: 12.6 g (83.0% of theory). C₁₂H₁₂BrNS (M=282.22). melting point:89° C.

3.60e 3-iodo-6,7,8,9-tetrahydro-5H-10-thia-7-aza-benzo[a]azulene

Prepared according to general working method II from3-bromo-6,7,8,9-tetrahydro-5H-10-thia-7-aza-benzo[a]azulene (1.80 g,6.38 mmol).

Yield: 1.80 g (85.7% of theory). C₁₂H₁₂INS (M=329.205). Calc.: molpeak(M+H)⁺: 330 Found: molpeak (M+H)⁺: 330. HPLC retention time: 5.45 min(method A).

3.60f3-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-6,7,8,9-tetrahydro-5H-10-thia-7-aza-benzo[a]azulene

Prepared according to general working method I from3-iodo-6,7,8,9-tetrahydro-5H-10-thia-7-aza-benzo[a]azulene (770 mg, 2.34mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (500 mg, 2.34 mmol).

Yield: 350 mg (36.0% of theory). C₂₅H₁₉ClN₂S (M=414.961). Calc.: molpeak(M+H)⁺: 415/417 Found: molpeak (M+H)⁺: 415/417. HPLC retention time:7.41 min (method A).

EXAMPLE 3.613-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-7-methyl-6,7,8,9-tetrahydro-5H-10-thia-7-aza-benzo[a]azulene

0.18 mL (2.41 mmol) 37% formalin solution in water are added to asolution of 100 mg (0.24 mmol)3-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-6,7,8,9-tetrahydro-5H-10-thia-7-aza-benzo[a]azulene(see 3.60f) in 5 mL acetonitrile. Then 60 mg (0.96 mmol) NaBH₃CN and 56μL (0.96 mmol) acetic acid are added and the reaction mixture is stirredovernight. The solution is combined with 2 M NaOH and extracted withEtOAc. The organic phase is dried over MgSO₄ and the solvent iseliminated i.vac. The purification is carried out by columnchromatography by HPLC-MS.

Yield: 3 mg (2.9% of theory). C₂₆H₂₁ClN₂S (M=428.988). Calc.: molpeak(M+H)⁺: 429/431 Found: molpeak (M+H)⁺: 429/431. HPLC retention time:4.97 min (method B).

EXAMPLE 3.625-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-1-(2-pyrrolidin-1-yl-ethyl)-1H-indazole

3.62a 5-nitro-1-(2-pyrrolidin-1-yl-ethyl)-1H-indazole and5-nitro-2-(2-pyrrolidin-1-yl-ethyl)-2H-indazole

10.5 g (62.0 mmol) 1-(2-chloroethyl)-pyrrolidine hydrochloride and 12.9g (93.0 mmol) K₂CO₃ are added successively to a solution of 5.00 g (31.0mmol) 5-nitroindazole in 100 mL acetonitrile. The reaction solution isstirred for 2 h at RT and refluxed for a further 5 h. After the solutionhas cooled the insoluble salts are filtered off and the solvent iseliminated i.vac. The residue is taken up in EtOAc and water. Theorganic phase is dried over MgSO₄ and the solvent is eliminated i.vac. A4:1 mixture of 5-nitro-1-(2-pyrrolidin-1-yl-ethyl)-1H-indazole and5-nitro-2-(2-pyrrolidin-1-yl-ethyl)-2H-indazole is obtained. Thepurification is carried out by column chromatography on Alox (PE/EtOAc3:2).

5-nitro-1-(2-pyrrolidin-1-yl-ethyl)-1H-indazole

Yield: 4.00 g (49.6% of theory). C₁₃H₁₆N₄O₂ (M=260.298). Calc.: molpeak(M+H)⁺: 261 Found: molpeak (M+H)⁺: 261. R_(f) value: 0.78 (Alox,PE/EtOAc 1:1).

5-nitro-2-(2-pyrrolidin-1-yl-ethyl)-2H-indazole

Yield: 1.00 g (12.4% of theory). C₁₃H₁₆N₄O₂ (M=260.298). Calc.: molpeak(M+H)⁺: 261 Found: molpeak (M+H)⁺: 261. R_(f) value: 0.61 (Alox,PE/EtOAc 1:1).

3.62b 1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-5-ylamine

0.50 g Raney nickel are added to a solution of 3.50 g (13.4 mmol)5-nitro-1-(2-pyrrolidin-1-yl-ethyl)-1H-indazole in 50 mL EtOAc and thereaction mixture is stirred for 20 h at RT at 1.4 bar H₂. Afterfiltration the solvent is eliminated i.vac. The product is furtherreacted without any more purification.

Yield: 2.90 g (93.6% of theory). C₁₃H₁₈N₄ (M=230.315). Calc.: molpeak(M+H)⁺: 231 Found: molpeak (M+H)⁺: 231.

3.62c 5-bromo-1-(2-pyrrolidin-1-yl-ethyl)-1H-indazole

1.00 g (4.34 mmol) 1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-5-ylamine isdissolved in 9.76 mL 48% hydrobromic acid and 9.76 mL water and thesolution is cooled to 0° C. 2.5 M sodium nitrite solution (300 mg in1.74 mL water) is slowly added dropwise. The reaction is stirred for 10min at 0° C. and then a solution of 935 mg (6.51 mmol) CuBr in 3.42 mL48% hydrobromic acid is added dropwise. The reaction is heated to 60° C.and stirred for one hour at this temperature. The mixture is dilutedwith water and the aqueous phase is extracted with EtOAc. The organicphase is discarded and the aqueous phase is made alkaline with saturatedNaHCO₃ solution. The aqueous phase is extracted with EtOAc and theorganic phase is washed with water. The organic phase is dried overMgSO₄ and the solvent is eliminated i.vac.

Yield: 500 mg (39.1% of theory). C₁₃H₁₆BrN₃ (M=294.197). Calc.: molpeak(M+H)⁺: 294/296 Found: molpeak (M+H)⁺: 294/296. R_(f) value: 0.59(silica gel, EtOAc/MeOH/NH₃ 9:1:0.1).

3.62d 5-iodo-1-(2-pyrrolidin-1-yl-ethyl)-1H-indazole

Prepared according to general working method II from5-bromo-1-(2-pyrrolidin-1-yl-ethyl)-1H-indazole (500 mg, 1.70 mmol).

Yield: 230 mg (39.7% of theory). C₁₃H₁₆IN₃ (M=341.197). Calc.: molpeak(M+H)⁺: 342 Found: molpeak (M+H)⁺: 342. R_(f) value: 0.55 (silica gel,DCM/MeOH 4:1).

3.62e5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-1-(2-pyrrolidin-1-yl-ethyl)-1H-indazolehydriodide

Prepared according to general working method I from5-iodo-1-(2-pyrrolidin-1-yl-ethyl)-1H-indazole (230 mg, 0.67 mmol) and5-(4-chloro-phenyl)-2-ethynyl-pyridine (144 mg, 0.67 mmol).

Yield: 90 mg (24.1% of theory). C₂₆H₂₃ClN₄.HI (M=554.865). Calc.:molpeak (M+H)⁺: 427/429 Found: molpeak (M+H)⁺: 427/429. HPLC retentiontime: 4.59 min (method B).

EXAMPLE 3.635-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-(2-pyrrolidin-1-yl-ethyl)-2H-indazole

3.63a 2-(2-pyrrolidin-1-yl-ethyl)-2H-indazol-5-ylamine

The product is obtained analogously to Example 3.62b from 1.0 g (3.84mmol) 5-nitro-2-(2-pyrrolidin-1-yl-ethyl)-2H-indazole (see 3.62a).

Yield: 840 mg (94.9% of theory). C₁₃H₁₈N₄ (M=230.315). Calc.: molpeak(M+H)⁺: 231 Found: molpeak (M+H)⁺: 231.

3.63b 5-bromo-2-(2-pyrrolidin-1-yl-ethyl)-2H-indazole

The product is obtained analogously to Example 3.62c from 840 mg (3.65mmol) 2-(2-pyrrolidin-1-yl-ethyl)-2H-indazol-5-ylamine.

Yield: 440 mg (41.0% of theory). C₁₃H₁₆BrN₃ (M=294.197). Calc.: molpeak(M+H)⁺: 294/296 Found: molpeak (M+H)⁺: 294/296. HPLC retention time:5.04 min (method A).

3.63c 5-iodo-2-(2-pyrrolidin-1-yl-ethyl)-2H-indazole

Prepared according to general working method II from5-bromo-2-(2-pyrrolidin-1-yl-ethyl)-2H-indazole (440 mg, 1.50 mmol).

Yield: 170 mg (33.3% of theory). C₁₃H₁₆IN₃ (M=341.197). Calc.: molpeak(M+H)⁺: 342 Found: molpeak (M+H)⁺: 342. R_(f) value: 0.40 (silica gel,DCM/MeOH 4:1).

3.63d5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-(2-pyrrolidin-1-yl-ethyl)-2H-indazole

Prepared according to general working method I from5-iodo-2-(2-pyrrolidin-1-yl-ethyl)-2H-indazole (170 mg, 0.50 mmol) and5-(4-chloro-phenyl)-2-ethynyl-pyridine (106 mg, 0.50 mmol).

Yield: 100 mg (42.3% of theory). C₂₆H₂₃ClN₄ (M=426.953). Calc.: molpeak(M+H)⁺: 427/429 Found: molpeak (M+H)⁺: 427/429. HPLC retention time:4.61 min (method B).

EXAMPLE 3.643-(4-chloro-phenyl)-6-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridazine

3.64a 3-chloro-6-(4-chloro-phenyl)-pyridazine

Under an argon atmosphere a solution of 11.3 g (70.5 mmol)4-chlorophenylboric acid in 50 mL 1,4-dioxane is added to a solution of10.8 g (70.5 mmol) 3,6-dichloropyridazine, 10 mL (20 mmol) of a 2 MNa₂CO₃ solution and 600 mg (0.73 mmol) Pd(dppf)Cl₂ in 150 mL 1,4-dioxaneat 110° C. over 2 h. The reaction mixture is stirred for 1 h at 110° C.100 mL water are added and the aqueous phase is extracted with 100 mLEtOAc. The organic phase is dried over Na₂SO₄ and the solvent iseliminated i.vac. Purification is carried out by column chromatographyon silica gel (cyc/EtOAc 4:1).

Yield: 8.00 g (50.4% of theory). C₁₀H₆Cl₂N₂ (M=225.079). Calc.: molpeak(M+H)⁺: 225/227/229 Found: molpeak (M+H)⁺: 225/227/229. HPLC retentiontime: 5.20 min (method A).

3.64b 3-(4-chloro-phenyl)-6-trimethylsilanylethynyl-pyridazine

Under an argon atmosphere 3.48 mL (25.0 mmol) triethylamine and 2.08 mL(15.0 mmol) ethynyl-trimethyl-silane are added successively to asolution of 2.25 g (10.0 mmol) 3-chloro-6-(4-chloro-phenyl)-pyridazinein 50 mL acetonitrile and 20 mL THF. Then 292 mg (0.40 mmol) Pd(dppf)Cl₂and 76 mg (0.40 mmol) CuI are added. The reaction solution is stirredovernight at RT. The solvent is eliminated i.vac. and furtherpurification is carried out by column chromatography on silica gel(PE/EtOAc 1:1).

Yield: 1.00 g (34.9% of theory). C₁₅H₁₅ClN₂Si (M=286.839). Calc.:molpeak (M+H)⁺: 287/289 Found: molpeak (M+H)⁺: 287/289. R_(f) value:0.45 (silica gel, DCM).

3.64c 3-(4-chloro-phenyl)-6-ethynyl-pyridazine

1.10 g (3.49 mmol) TBAF are added at 0° C. to a solution of 1.00 g (3.49mmol) 3-(4-chloro-phenyl)-6-trimethylsilanylethynyl-pyridazine in 10 mLDCM. The ice bath is removed and the reaction solution is stirred for 30min. Water is added and the aqueous phase is extracted with EtOAc. Theorganic phase is dried over MgSO₄ and the solvent is eliminated i.vac.The product is reacted without any further purification.

Yield: 700 mg (93.5% of theory). C₁₂H₇ClN₂ (M=214.656). Calc.: molpeak(M+H)⁺: 215/217 Found: molpeak (M+H)⁺: 215/217. HPLC retention time:5.16 min (method B).

3.64d3-(4-chloro-phenyl)-6-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridazine

Prepared according to general working method I from1-[2-(4-iodo-phenoxy)-ethyl]-pyrrolidine (200 mg, 0.63 mmol) and3-(4-chloro-phenyl)-6-ethynyl-pyridazine (135 mg, 0.63 mmol).

Yield: 15 mg (5.9% of theory). C₂₄H₂₂ClN₃O (M=403.915). Calc.: molpeak(M+H)⁺: 404/406 Found: molpeak (M+H)⁺: 404/406. HPLC retention time:5.01 min (method A).

EXAMPLE 3.655-(4-chloro-phenyl)-3-fluoro-2-{4-[2-(4-methyl-piperidin-1-yl)-ethoxy]-phenylethynyl}-pyridine

3.65a 1-[2-(4-iodo-phenoxy)-ethyl]-4-methyl-piperidine

The product is obtained analogously to Example 3.1e from 5.72 g (26.0mmol) 4-iodo-phenol and 4.20 g (26.0 mmol)1-(2-chloro-ethyl)-4-methyl-piperidine.

Yield: 2.60 g (29.0% of theory). C₁₄H₂₀INO (M=345.226). Calc.: molpeak(M+H)⁺: 346 Found: molpeak (M+H)⁺: 346. HPLC retention time: 5.70 min(method A).

3.65b 5-(4-chloro-phenyl)-3-nitro-pyridin-2-ol

23.5 g (150 mmol) 4-chlorophenyl-boric acid are added under argon to asolution of 22.1 g (101 mmol) 5-bromo-3-nitro-pyridin-2-ol, 200 mL (400mmol) of a 2 M Na₂CO₃ solution and 731 mg (1.00 mmol) Pd(dppf)Cl₂ in 400mL acetone and 80 mL water. The reaction mixture is stirred for 18 h at60° C. Acetone is eliminated i.vac. and the residue is adjusted to pH 7with 160 mL 1 M citric acid. The aqueous phase is extracted three timeswith EtOAc and once with MeOH. The organic phase is dried over MgSO₄ andthe solvent is eliminated i.vac. The residue is triturated with EtOAc.

Yield: 9.70 g (22.0% of theory). C₁₁H₇ClN₂O₃ (M=250.643). Calc.: molpeak(M−H)⁻: 249/251 Found: molpeak (M−H)⁻: 249/251. HPLC retention time:6.83 min (method A).

3.65c 2-bromo-5-(4-chloro-phenyl)-3-nitro-pyridine

13.2 g (93.0 mmol) phosphorus pentoxide are added to a solution of 9.70g (38.7 mmol) 5-(4-chloro-phenyl)-3-nitro-pyridin-2-ol and 14.5 mmol(45.0 mmol) tetrabutylammonium bromide in 100 mL toluene. The reactionmixture is stirred for 1.5 h at 95° C. After cooling the toluene phaseis decanted off and the residue is twice combined with toluene anddecanted off. The combined organic phases are washed with saturatedNaHCO₃ solution. The organic phase is dried over MgSO₄ and the solventis eliminated i.vac. The product is further reacted without any morepurification.

Yield: 4.90 g (40.4% of theory). C₁₁H₆BrClN₂O₂ (M=313.540). Calc.:molpeak (M+H)⁺: 313/315/317 Found: molpeak (M+H)⁺: 313/315/317. HPLCretention time: 6.01 min (method B).

3.65d 2-bromo-5-(4-chloro-phenyl)-pyridin-3-ylamine

A solution of 5.60 g (17.9 mmol)2-bromo-5-(4-chloro-phenyl)-3-nitro-pyridine, 20.3 g (90.0 mmol)tin(II)-chloride and 18.9 g (225 mmol) NaHCO₃ in 300 mL EtOAc isrefluxed for 30 h. After filtration the solvent is eliminated i.vac. Theresidue is triturated with DCM and after filtration the filter residueis dried in the air.

Yield: 3.50 g (69.1% of theory). C₁₁H₈BrClN₂ (M=283.557). Calc.: molpeak(M+H)⁺: 283/285/287 Found: molpeak (M+H)⁺: 283/285/287. HPLC retentiontime: 5.45 min (method B).

3.65e 2-bromo-5-(4-chloro-phenyl)-3-fluoro-pyridine

243 mg (3.53 mmol) sodium nitrite in 0.5 mL water are added dropwise at−5° C. to a solution of 1.00 g (3.53 mmol)2-bromo-5-(4-chloro-phenyl)-pyridin-3-ylamine in 2 mL water and 2.04 mLconcentrated HCl. Then at 0° C. 1.56 mL (10.6 mmol) 60%hexafluorophosphoric acid in water are added and the reaction is stirredfor a further hour at 0° C. The diazonium salt is suction filtered,washed with cold water, isopropanol and ether and dried overnight in thedesiccator at RT and 7 mbar. This is then added batchwise at 90° C. to50 mL PE (boiling point 100-140° C.). After the reaction solution hascooled the mixture is made alkaline with saturated Na₂CO₃ solution. Theaqueous phase is extracted with EtOAc and the organic phase is washedsuccessively with saturated Na₂CO₃ solution and water. The organic phaseis dried over MgSO₄ and the solvent is eliminated i.vac. Thepurification is carried out by column chromatography on silica gel (PE).

Yield: 460 mg (45.5% of theory). C₁₁H₆BrClFN (M=286.533). Calc.: molpeak(M+H)⁺: 286/288/290 Found: molpeak (M+H)⁺: 286/288/290. HPLC retentiontime: 6.24 min (method B).

3.65f 5-(4-chloro-phenyl)-3-fluoro-2-trimethylsilanylethynyl-pyridine

The product is obtained analogously to Example 3.64b from 460 mg (1.61mmol) 2-bromo-5-(4-chloro-phenyl)-3-fluoro-pyridine and 0.33 mL (2.41mmol) ethynyl-trimethyl-silane.

Yield: 490 mg (100% of theory). C₁₆H₁₅ClFNSi (M=303.842). Calc.: molpeak(M+H)⁺: 304/306 Found: molpeak (M+H)⁺: 304/306.

3.65g 5-(4-chloro-phenyl)-2-ethynyl-3-fluoro-pyridine

The product is obtained analogously to Example 3.64c from 490 mg (1.61mmol) 5-(4-chloro-phenyl)-3-fluoro-2-trimethylsilanylethynyl-pyridine.

Yield: 300 mg (57.4% of theory). C₁₃H₇ClFN (M=231.659). Calc.: molpeak(M+H)⁺: 232/234 Found: molpeak (M+H)⁺: 232/234.

3.65h5-(4-chloro-phenyl)-3-fluoro-2-{4-[2-(4-methyl-piperidin-1-yl)-ethoxy]-phenylethynyl}-pyridine

Prepared according to general working method I from1-[2-(4-iodo-phenoxy)-ethyl]-4-methyl-piperidine (164 mg, 0.48 mmol) and5-(4-chloro-phenyl)-2-ethynyl-3-fluoro-pyridine (110 mg, 0.48 mmol).

Yield: 14 mg (6.6% of theory). C₂₇H₂₆ClFN₂O (M=448.972). Calc.: molpeak(M+H)⁺: 449/451 Found: molpeak (M+H)⁺: 449/451. HPLC retention time:5.16 min (method B).

EXAMPLE 3.666-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-1-methanesulphonyl-2-pyrrolidin-1-ylmethyl-1,2,3,4-tetrahydro-quinoline

0.13 mL (0.93 mmol) triethylamine and 36 μL (0.47 mmol) methanesulphonicacid chloride are added successively at 0° C. to a solution of 200 mg(0.47 mmol)6-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-pyrrolidin-1-ylmethyl-1,2,3,4-tetrahydro-quinoline(see Example 3.46) in 5 mL DCM. The reaction mixture is heated to RT andstirred for a further hour at this temperature. Another 36 μL (0.47mmol) methanesulphonic acid chloride are added and the mixture isstirred for a further hour at RT. The reaction mixture is poured ontowater and exhaustively extracted with DCM. The organic phase is driedover MgSO₄ and the solvent is eliminated i.vac. The purification iscarried out by column chromatography using HPLC-MS.

Yield: 9 mg (3.8% of theory). C₂₈H₂₈ClN₃O₂S (M=506.071). Calc.: molpeak(M+H)⁺: 506/508 Found: molpeak (M+H)⁺: 506/508. HPLC retention time:5.26 min (column from method A; isocratic: 30% acetonitrile).

EXAMPLE 3.671-{6-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-pyrrolidin-1-ylmethyl-3,4-dihydro-2H-quinolin-1-yl}-ethanone

74 μL (0.77 mmol) acetic anhydride are added to a solution of 220 mg(0.51 mmol)6-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-pyrrolidin-1-ylmethyl-1,2,3,4-tetrahydro-quinoline(see Example 3.46) in 5 mL DCM and the mixture is stirred for 2 h at RT.Another 0.37 mL (3.85 mmol) acetic anhydride are added and the reactionis stirred for a further 4 days at RT. The solvent is eliminated i.vac.The purification is carried out by column chromatography using HPLC-MS.

Yield: 105 mg (43.5% of theory). C₂₉H₂₈ClN₃O (M=470.019). Calc.: molpeak(M+H)⁺: 470/472 Found: molpeak (M+H)⁺: 470/472. HPLC retention time:7.08 min (method A).

EXAMPLE 3.685-(4-chloro-phenyl)-2-[3-pyridin-2-yl-4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridine

30 mg (0.24 mmol) pyridine-3-boric acid are added to a solution of 115mg (0.24 mmol)2-[3-bromo-4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-5-(4-chloro-phenyl)-pyridine(see Example 3.7), 0.5 mL (1.00 mmol) of a 2 M Na₂CO₃ solution and 15 mg(0.24 mmol) tetrakis-triphenylphosphane-palladium in 1 mL 1,4-dioxaneand 0.3 mL methanol. The reaction mixture is refluxed for 6 h. Afterfiltration the solvent is eliminated i.vac. The purification is carriedout by column chromatography on silica gel (gradient: DCM toDCM/MeOH/NH₃ 1:1:0.1).

Yield: 1.8 mg (1.6% of theory). C₃₀H₂₆ClN₃O (M=480.01). Calc.: molpeak(M−H)⁻: 480/482 Found: molpeak (M−H)⁻: 480/482. HPLC retention time:6.50 min (method A).

EXAMPLE 3.695-(4-chloro-phenyl)-2-{4-[2-(4-methyl-piperidin-1-yl)-ethoxy]-naphthyl-1-ylethynyl}-pyridine

3.69a 1-[2-(4-bromo-naphthyl-1-yloxy)-ethyl]-4-methyl-piperidin

The product is obtained analogously to Example 3.1e from 1.0 g (5.35mmol) 4-bromo-naphthyl-1-ol and 323 mg (2.00 mmol)1-(2-chloro-ethyl)-4-methyl-piperidine.

Yield: 530 mg (97.0% of theory). C₁₈H₂₂BrNO (M=348.286). Calc.: molpeak(M+H)⁺: 348/350 Found: molpeak (M+H)⁺: 348/350. HPLC retention time:7.10 min (method A).

3.69b 1-[2-(4-iodo-naphthyl-1-yloxy)-ethyl]-4-methyl-piperidine

Prepared according to general working method II from1-[2-(4-bromo-naphthyl-1-yloxy)-ethyl]-4-methyl-piperidine (530 mg, 1.52mmol).

Yield: 500 mg (83.1% of theory). C₁₈H₂₂INO (M=395.287). Calc.: molpeak(M+H)⁺: 396 Found: molpeak (M+H)⁺: 396. HPLC retention time: 6.74 min(method A).

3.69c5-(4-chloro-phenyl)-2-{4-[2-(4-methyl-piperidin-1-yl)-ethoxy]-naphthyl-1-ylethynyl}-pyridine

Prepared according to general working method I from1-[2-(4-iodo-naphthyl-1-yloxy)-ethyl]-4-methyl-piperidine (277 mg, 0.70mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (150 mg, 0.70 mmol).

Yield: 66 mg (19.6% of theory). C₃₁H₂₉ClN₂O (M=481.043). Calc.: molpeak(M+H)⁺: 481/483 Found: molpeak (M+H)⁺: 481/483. R_(f) value: 0.60(silica gel, EtOAc/MeOH/NH₃ 95:5:0.5).

EXAMPLE 3.702-{4-[2-(4-methyl-piperidin-1-yl)-ethoxy]-phenylethynyl}-5-phenyl-pyridine

3.70a5-bromo-2-{4-[2-(4-methyl-piperidin-1-yl)-ethoxy]-phenylethynyl}-pyridine

Prepared according to general working method I from1-[2-(4-iodo-phenoxy)-ethyl]-4-methyl-piperidine (345 mg, 1.00 mmol) and5-bromo-2-ethynyl-pyridine (83 mg, 0.39 mmol).

Yield: 100 mg (25.0% of theory). C₂₁H₂₃BrN₂O (M=399.334). Calc.: molpeak(M+H)⁺: 399/401 Found: molpeak (M+H)⁺: 399/401. R_(f) value: 0.83(silica gel, DCM/MeOH/NH₃ 95:5:0.5).

3.70.b2-{4-[2-(4-methyl-piperidin-1-yl)-ethoxy]-phenylethynyl}-5-phenyl-pyridine

Under an argon atmosphere 30 mg (0.25 mmol) phenylboric acid are addedto a solution of 100 mg (0.25 mmol)5-bromo-2-{4-[2-(4-methyl-piperidin-1-yl)-ethoxy]-phenylethynyl}-pyridine,0.25 mL (0.50 mmol) of a 2 M Na₂CO₃ solution and 4 mg (0.01 mmol)Pd(dppf)Cl₂ in 5 mL 1,4-dioxane and 2 mL MeOH. The reaction mixture isstirred for 3 days at 90° C. The reaction mixture is diluted with EtOAcand the organic phase is washed with 40 mL water and finally withsaturated NaCl solution. The organic phase is dried over MgSO₄ and thesolvent is eliminated i.vac. The purification is carried out usingHPLC-MS and by column chromatography on silica gel (gradient:DCM/MeOH/NH3 95:5:0.5 to DCM/MeOH/NH₃ 9:1:0.1).

Yield: 27 mg (27.2% of theory). C₂₇H₂₈N₂O (M=396.537). Calc.: molpeak(M+H)⁺: 397 Found: molpeak (M+H)⁺: 397. HPLC retention time: 7.61 min(method A).

EXAMPLE 3.715-(4-chloro-phenyl)-2-{4-[2-(4-methyl-piperidin-1-yl)-propoxy]-phenylethynyl}-pyridine

3.71a 1-(4-iodo-phenoxy)-propan-2-ol

The product is obtained analogously to Example 3.1e from 1.39 g (10.0mmol) 1-bromo-2-propanol and 2.20 g (10.0 mmol) 4-iodophenol.

Yield: 2.00 g (71.9% of theory). C₉H₁₁IO₂ (M=278.091). Calc.: molpeak(M+Na)⁺: 301 Found: molpeak (M+Na)⁺: 301. R_(f) value: 0.20 (silica gel,PE/EtOAc 4:1)

3.71b1-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-propan-2-ol

Prepared according to general working method I from1-(4-iodo-phenoxy)-propan-2-ol (2.00 g, 7.19 mmol) and5-(4-chloro-phenyl)-2-ethynyl-pyridine (1.54 g, 7.20 mmol).

Yield: 1.50 g (57.3% of theory). C₂₂H₁₈ClNO₂ (M=363.847). Calc.: molpeak(M+H)⁺: 364/366 Found: molpeak (M+H)⁺: 364/366. R_(f) value: 0.25(silica gel, PE/EtOAc/DCM 1:1:8).

3.71c2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-1-methyl-ethylmethanesulphonate

0.35 mL (4.50 mmol) methanesulphonic acid chloride are added at RT to asolution of 1.50 g (4.12 mmol)1-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-propan-2-ol and1.14 mL (8.20 mmol) triethylamine in 80 mL THF and the reaction isstirred for 3 h at this temperature. The solvent is eliminated i.vac.and the residue is combined with 40 mL tert-butylmethylether and 60 mLwater. The precipitate is suction filtered-and further purification iscarried out by column chromatography on silica gel (EtOAc).

Yield: 1.00 g (54.9% of theory). C₂₃H₂₀ClNO₄S (M=441.937). Calc.:molpeak (M+H)⁺: 442/444 Found: molpeak (M+H)⁺: 442/444. R_(f) value:0.78 (silica gel, PE/EtOAc/DCM 1:1:8).

3.71d5-(4-chloro-phenyl)-2-{4-[2-(4-methyl-piperidin-1-yl)-propoxy]-phenylethynyl}-pyridine

0.21 mL (1.80 mmol) 4-methylpiperidine are added to a solution of 133 mg(0.30 mmol)2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-1-methyl-ethylmethanesulphonate in 2 mL DMF and the mixture is stirred for 16 h at 60°C. and 6 h at 80° C. The solvent is eliminated i.vac., the residue istriturated with isopropanol, suction filtered and dried at 30° C. in thecirculating air dryer.

Yield: 65 mg (48.7% of theory). C₂₈H₂₉ClN₂O (M=445.009). Calc.: molpeak(M+H)⁺: 445/447 Found: molpeak (M+H)⁺: 445/447. HPLC retention time:5.37 min (method B).

EXAMPLE 3.72(1-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-pyrrolidin-3-yl)-4-methylpiperidine

3.72a (R)-1-(5-bromo-pyridin-2-yl)-pyrrolidin-3-ol

The product is obtained analogously to Example 3.31a (reaction time: 60min at 140° C.) from 2.72 g (11.5 mmol) 2,5-dibromopyridine and 1.00 g(11.5 mmol) (R)-3-pyrrolidinole.

Yield: 1.20 g (43.0% of theory). C₉H₁₁BrN₂O (M=243.105). Calc.: molpeak(M+H)⁺: 242/244 Found: molpeak (M+H)⁺: 242/244. HPLC retention time:3.43 min (method A).

3.72b (R)-1-(5-iodo-pyridin-2-yl)-pyrrolidin-3-ol

Prepared according to general working method II from(R)-1-(5-bromo-pyridin-2-yl)-pyrrolidin-3-ol (1.20 g, 4.94 mmol).

Yield: 1.30 g (90.8% of theory). C₉H₁₁IN₂O (M=290.105). Calc.: molpeak(M+H)⁺: 291 Found: molpeak (M+H)⁺: 291. HPLC retention time: 3.48 min(method A).

3.72c(R)-1-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-pyrrolidin-3-ol

Prepared according to general working method I from(R)-1-(5-iodo-pyridin-2-yl)-pyrrolidin-3-ol (1.30 g, 4.48 mmol) and5-(4-chloro-phenyl)-2-ethynyl-pyridine (957 mg, 4.48 mmol).

Yield: 1.36 g (80.7% of theory). C₂₂H₁₈ClN₃O (M=375.861). Calc.: molpeak(M+H)⁺: 376/378 Found: molpeak (M+H)⁺: 376/378. HPLC retention time:6.76 min (method A).

3.72d1-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-pyrrolidin-3-one

0.43 mL (5.32 mmol) pyridine and 2.26 g (0.80 mmol, 15 percent byweight) Dess-Martin-periodinane in DCM are added to a solution of 200 mg(0.53 mmol)(R)-1-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-pyrrolidin-3-olin 10 mL DCM. The reaction mixture is stirred for 3 h at RT and added toa solution of semisaturated NaHCO₃ solution and tert-butylmethylether.The aqueous phase is extracted twice with EtOAc. The organic phase isdried over MgSO₄ and the solvent is eliminated i.vac. The product isfurther reacted without purification.

Yield: 100 mg (35.2% of theory). C₂₂H₁₆ClN₃O (M=373.845). Calc.: molpeak(M+H)⁺: 374/376 Found: molpeak (M+H)⁺: 374/376.

3.72e(1-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-pyrrolidin-3-yl)-4-methylpiperidine

48 mg (0.22 mmol) NaBH(OAc)₃ and 27 μL (0.47 mmol) acetic acid are addedto a solution of 100 mg (0.19 mmol, 70% purity)1-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-pyrrolidin-3-oneand 22 μL 4-methylpiperidine (0.19 mmol) in 5 mL THF. The reactionmixture is stirred overnight and combined with saturated NaHCO₃solution. The organic phase is extracted twice with EtOAc. The organicphase is dried over MgSO₄ and the solvent is eliminated i.vac. Furtherpurification is carried out by column chromatography using HPLC-MS.

Yield: 11 mg (12.9% of theory). C₂₈H₂₉ClN₄ (M=457.023). Calc.: molpeak(M+H)⁺: 457/459 Found: molpeak (M+H)⁺: 457/459. HPLC retention time:5.19 min (method A).

EXAMPLE 3.735-(4-chloro-phenyl)-2-[4-(3-pyrrolidin-1-yl-prop-1-ynyl)-phenylethynyl]-pyridine

3.73a 1-[3-(4-bromo-phenyl)-prop-2-ynyl]-pyrrolidine

Prepared according to general working method I from 4-bromo-iodobenzene(10.9 g, 38.5 mmol) and 1-prop-2-ynyl-pyrrolidine (4.20 g, 71% purity,27.3 mmol).

Yield: 6.40 g (88.7% of theory). C₁₃H₁₄BrN (M=264.167). Calc.: molpeak(M+H)⁺: 264/266 Found: molpeak (M+H)⁺: 264/266.

3.73b 1-[3-(4-iodo-phenyl)-prop-2-ynyl]-pyrrolidine

Prepared according to general working method II from1-[3-(4-bromo-phenyl)-prop-2-ynyl]-pyrrolidine (3.2 g, 12.1 mmol).

Yield: 230 mg (4.6% of theory). C₁₃H₁₄IN (M=311.168). Calc.: molpeak(M+H)⁺: 312 Found: molpeak (M+H)⁺: 312.

3.73c5-(4-chloro-phenyl)-2-[4-(3-pyrrolidin-1-yl-prop-1-ynyl)-phenylethynyl]-pyridine

Prepared according to general working method I from1-[3-(4-iodo-phenyl)-prop-2-ynyl]-pyrrolidine (230 mg, 75%, 0.55 mmol)and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (118 mg, 0.55 mmol).

Yield: 96 mg (43.7% of theory). C₂₆H₂₁ClN₂ (M=396.924). Calc.: molpeak(M+H)⁺: 397/399 Found: molpeak (M+H)⁺: 397/399. HPLC retention time:5.03 min (method B).

EXAMPLE 3.746-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-1-methyl-2-pyrrolidin-1-ylmethyl-1,2,3,4-tetrahydro-quinoline

37 mg (1.23 mmol) paraformaldehyde in 1.8 mL THF are added to a solutionof 350 mg (0.82 mmol)6-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-pyrrolidin-1-ylmethyl-1,2,3,4-tetrahydro-quinoline(see Example 3.46) in 1.6 mL THF. 0.24 mL acetic acid and 1.2 mL THF areadded to this mixture. Finally, 1.00 g (2.05 mmol) cyanoborohydrideresin (macroporous polystyrene, load: 2.04 mmol/g) are added and themixture is stirred for 16 h at RT. After filtration the filtrate iscombined with 1.50 g (2.15 mmol) toluenesulphonic acid resin(macroporous polystyrene, load: 1.43 mmol/g), shaken for 30 min andsuction filtered. The solvent is eliminated i.vac. and purification iscarried out by column chromatography using HPLC-MS.

Yield: 33 mg (9.1% of theory). C₂₈H₂₈ClN₃ (M=442.008). Calc.: molpeak(M+H)⁺: 442/444 Found: molpeak (M+H)⁺: 442/444. HPLC retention time:5.22 min (method B).

EXAMPLE 45-(4-chloro-phenyl)-2-{4-[2-(2,5-dihydro-pyrrol-1-yl)-ethoxy]-phenylethynyl}-pyridine

4a 2-(4-iodo-phenoxy)-ethanol

A suspension of 11 g (50 mmol) 4-iodophenol, 3.88 mL (55 mmol)2-bromoethanol and 8.3 g (60 mmol) K₂CO₃ in 60 mL acetone is refluxedfor 24 h. The solvent is eliminated i.vac., the residue is combined withwater, exhaustively extracted with EtOAc and the organic phase is driedover Na₂SO₄. After the desiccant and solvent have been eliminated theresidue is purified by chromatography on silica gel (cyc/EtOAc 7:3).

Yield: 2.9 g (22.0% of theory). C₈H₉IO₂ (M=264.064). Calc.: molpeak(M+H)⁺: 264 Found: molpeak (M+H)⁺: 264. R_(f) value: 0.24 (silica gel,cyc/EtOAc 2:1).

4b 2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-ethanol

Under an argon atmosphere 253 mg (0.22 mmol)tetrakis-triphenylphosphane-palladium and 42 mg (0.22 mmol) CuI areadded to a solution of 2.9 g (11 mmol) 2-(4-iodo-phenoxy)-ethanol and2.35 g (11 mmol) 5-(4-chloro-phenyl)-2-ethynyl-pyridine in 50 mLpiperidine and the reaction mixture is stirred for 30 min at RT. Thesolvent is eliminated i.vac., the residue is combined with water andstirred with EtOAc. The product precipitated is suction filtered anddried.

Yield: 2.1 g (54.7% of theory). C₂₁H₁₆ClNO₂ (M=349.820). Calc.: molpeak(M+H)⁺: 350 Found: molpeak (M+H)⁺: 350. R_(f) value: 0.42 (silica gel,cyc/EtOAc 1:1).

4c5-(4-chloro-phenyl)-2-{4-[2-(2,5-dihydro-pyrrol-1-yl)-ethoxy]-phenylethynyl}-pyridine

23 μL (0.29 mmol) methanesulphonic acid chloride are added dropwise to asolution, cooled to 0° C., of 85 mg (0.24 mmol)2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-ethanol and 41μL (0.29 mmol) triethylamine in 10 mL DCM and the reaction mixture isstirred for 1 h at this temperature. 46 μL (0.58 mmol)2,5-dihydro-1H-pyrrole are added dropwise, the mixture is heated to RTand stirred overnight. 1 mL of DMF is added and the mixture is heatedfor 8 h to 70° C. The mixture is evaporated down i.vac., the residue iscombined with water, extracted exhaustively with EtOAc and the organicphase is dried over Na₂SO₄. After the desiccant and solvent have beeneliminated the residue is purified by chromatography on silica gel(EtOAc/MeOH/NH₃ 95:5:0.5).

Yield: 16 mg (16.4% of theory). C₂₅H₂₁ClN₂O (M=400.912). Calc.: molpeak(M+H)⁺: 401/403 Found: molpeak (M+H)⁺: 401/403. R_(f) value: 0.16(silica gel, DCM/MeOH 95:5).

EXAMPLE 4.15-(4-chloro-phenyl)-2-[4-(2-piperidin-1-yl-ethoxy)-phenylethynyl]-pyridine

4.1a 2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-ethylmethanesulphonate

0.59 mL (7.55 mmol) methanesulphonic acid chloride are added dropwise toa solution, cooled to 0° C., of 2.2 g (6.29 mmol)2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-ethanol and 1.74mL (12.58 mmol) triethylamine in 25 mL THF. The reaction mixture isheated to RT and stirred for 2 h. To complete the reaction 5 mL pyridineare added and kept at RT for a further 18 h. The solvent is eliminatedi.vac., the residue is combined with water and triturated with diethylether. The product precipitated is suction filtered and dried.

Yield: 2.4 g (89.2% of theory). C₂₂H₁₈ClNO₄S (M=427.910). Calc.: molpeak(M+H)⁺: 428/430 Found: molpeak (M+H)⁺: 428/430. R_(f) value: 0.42(silica gel, cyc/EtOAc 1:1).

4.1b5-(4-chloro-phenyl)-2-[4-(2-piperidin-1-yl-ethoxy)-phenylethynyl]-pyridine

99 μL (1.0 mmol) piperidine are added to a solution of 85.6 mg (0.2mmol) of 2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-ethylmethanesulphonate in 2 mL DMF and the reaction mixture is stirred for 18h at RT. The solvent is distilled off i.vac., the residue is stirredwith 5 mL water and 40 mL DCM, the organic phase is separated off anddried with Na₂SO₄. After the desiccant and solvent have been eliminatedthe residue is triturated with 20 mL diethyl ether and suction filtered.

Yield: 62 mg (74.3% of theory). C₂₆H₂₅ClN₂O (M=416.955). Calc.: molpeak(M+H)⁺: 417/419 Found: molpeak (M+H)⁺: 417/419. HPLC retention time:6.51 min (method A).

The following compounds are prepared as described in Example 4.1b:

HPLC retention time empirical mass in min Example R Yield (%) formulaspectrum (method) 4.2

48.9 C₂₄H₂₁ClN₂O 389/391[M + H]⁺ 6.15 (A) 4.3

27.5 C₂₈H₂₄ClN₃O 454/456[M + H]⁺ 7.25 (A) 4.4

28.4 C₂₇H₂₂ClN₃O 440/442[M + H]⁺ 7.46 (A) 4.5

50.3 C₂₇H₂₇ClN₂O₂ 447/449[M + H]⁺ 7.46 (A) 4.6

27.2 C₂₈H₃₀ClN₃O 460/462[M + H]⁺ 5.86 (A) 4.7

69.9 C₃₀H₂₅ClN₂O 465/467[M + H]⁺ 7.98 (A) 4.8

55.8 C₂₅H₂₃ClN₂O 403/405[M + H]⁺ 6.24 (A) 4.9

72.0 C₃₀H₃₂ClN₃O 486/488[M + H]⁺ 5.54 (A) 4.10

65.6 C₂₅H₂₃ClN₂O₂ 418/420[M + H]⁺ 6.38 (A) 4.11

48.6 C₂₆H₂₆ClN₃O 432/434[M + H]⁺ 5.78 (A) 4.12

50.3 C₂₇H₂₇ClN₂O₂ 447/449[M + H]⁺ 0.80(EtOAc/MeOH/NH₃90:10:1) 4.13

33.0 C₃₂H₃₆ClN₃O₃ 546/548[M + H]⁺ 0.75(EtOAc/MeOH/NH₃90:10:1) 4.14

54.0 C₂₆H₂₅ClN₂O 417/419[M + H]⁺ 0.78(EtOAc/MeOH/NH₃90:10:1)

The following compounds are prepared as described in Example 4.1b, whileafter the elimination of the solvent the reaction mixture is combinedwith 5 mL saturated NaHCO₃ solution, extracted with 40 mL DCM and afterthe organic phase has been removed it is dried with Na₂SO₄. After thedesiccant and solvent have been eliminated the residue is purified bychromatography on silica gel.

HPLC retention empirical mass time in min Example R Yield (%) formulaspectrum (method) 4.15

57.9 C₃₀H₃₂ClN₃O₃ 518/520[M + H]⁺ 7.94 (A) 4.16

73.7 C₂₄H₂₃ClN₂O₂ 407/409[M + H]⁺ 6.29 (A) 4.17

61.8 C₂₉H₂₅ClN₂O 453/455[M + H]⁺ 7.81 (A)

3 eq. of the corresponding amine are added to a solution of 1 eq.2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-ethylmethanesulphonate in DMF (2 mL/0.25 mmol) and the reaction mixture isstirred for 16-72 h at 60-70° C. The working up is done by 2 alternativemethods:

Alternative A: The reaction mixture is purified directly by HPLC.

Alternative B: After the reaction mixture has cooled the precipitateformed is combined with 1.5 mL isopropanol, suction filtered, washedwith a little isopropanol and dried overnight at 30° C. in thecirculating air dryer.

The following compounds are obtained by this method:

HPLC retention time Yield (%) empirical mass in min Example R (variant)formula spectrum (method) 4.18

53.6 (A) C₃₃H₃₈ClN₃O₃ 560/562[M + H]⁺ 5.44 (B) 4.19

37.6 (A) C₃₁H₃₄ClN₃O₃ 532/534[M + H]⁺ 5.24 (B) 4.20

42.1 (A) C₂₇H₂₇ClN₂O₂ 447/449[M + H]⁺ 7.19 (A) 4.21

41.3 (A) C₂₈H₂₉ClN₂O 445/447[M + H]⁺ 7.95 (A) 4.22

40.3 (A) C₂₇H₂₇ClN₂O₂ 447/449[M + H]⁺ 4.68 (B) 4.23

69.3 (A) C₃₀H₃₂ClN₃O₂ 502/504[M + H]⁺ 6.86 (A) 4.24

70.2 (A) C₂₆H₂₅ClN₂O₂ 433/435[M + H]⁺ 4.68 (A) 4.25

27.0 (A) C₂₈H₂₉ClN₂O 445/447[M + H]⁺ 5.30 (B) 4.26

23.4 (A) C₂₈H₂₉ClN₂O 445/447[M + H]⁺ 8.09 (A) 4.27

70.7 (A) C₂₇H₂₇ClN₂O₂ 447/449[M + H]⁺ 6.79 (A) 4.28

20.0 (B) C₂₉H₃₁ClN₂O 459/461[M + H]⁺ 5.49 (B) 4.29

66.6 (B) C₃₆H₄₂ClN₃O₃ 600/602[M + H]⁺ 5.70 (B) 4.30

9.2 (A) C₂₇H₂₉ClN₂O 433/435[M + H]⁺ 5.20 (B) 4.31

22.9 (A) C₃₀H₃₄ClN₃O 488/490[M + H]⁺ 5.60 (A) 4.32

87.0 (B) C₂₇H₂₆ClN₃O₂ 460/462[M + H]⁺ 0.12(DCM/MeOH/NH₃95:5:0.5) 4.33

48.0 (B) C₂₆H₂₅ClN₂O₂ 433/435[M + H]⁺ 0.13(DCM/MeOH/NH₃95:5:0.5) 4.34

39.0 (B) C₂₇H₂₇ClN₂O 431/433[M + H]⁺ 0.28(DCM/MeOH/NH₃95:5:0.5) 4.35

61.7 (B) C₃₁H₂₉ClN₂O 493/495[M + H]⁺ 0.35(DCM/MeOH/NH₃95:5:0.5) 4.36

20.4 (B) C₃₀H₃₁ClN₂O 471/473[M + H]⁺ 0.25(DCM/MeOH/NH₃95:5:0.5) 4.37

75.6 (B) C₃₀H₃₁ClN₂O 471/473[M + H]⁺ 0.23(DCM/MeOH/NH₃95:5:0.5) 4.38

69.0 (B) C₃₁H₃₄ClN₃O₂ 516/518[M + H]⁺ 0.20(DCM/MeOH/NH₃95:5:0.5) 4.39

40.5 (B) C₂₆H₂₃ClN₂O 415/417[M + H]⁺ 0.22(DCM/MeOH/NH₃95:5:0.5) 4.40

63.5 (B) C₂₉H₂₅ClN₂OS 485/487[M + H]⁺ 0.18(DCM/MeOH/NH₃9:1:0.1) 4.41

38.8 (B) C₂₉H₃₂ClN₃O 474/476[M + H]⁺ 0.09(DCM/MeOH/NH₃95:5:0.5) 4.42

41.7 (B) C₃₀H₃₁ClN₂O 471/473[M + H]⁺ 0.30(DCM/MeOH/NH₃95:5:0.5) 4.43

55.8 (B) C₂₉H₃₁ClN₂O 459/461[M + H]⁺ 0.23(DCM/MeOH/NH₃95:5:0.5) 4.44

29.7 (B) C₂₈H₂₉ClN₂O 445/447[M + H]⁺ 0.32(DCM/MeOH/NH₃95:5:0.5)

EXAMPLE 4.451-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-ethyl)-[4,4′]bipiperidine

3 mL of a 5 N HCl solution in isopropanol are added to a solution of 200mg (0.33 mmol) tert-butyl1′-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-ethyl)-[4,4′]bipiperidinyl-1-carboxylate(Example 4.29) in 5 mL DCM and the reaction mixture is stirred for 4 hat RT. It is diluted with 30 mL DCM, neutralised with saturated NaHCO₃solution, combined with 30 mL water, the aqueous phase is extractedexhaustively with DCM and the combined organic phases are dried overMgSO₄. After the desiccant and solvent have been eliminated the desiredproduct is obtained.

Yield: 127 mg (76.3% of theory). C₃₁H₃₄ClN₃O (M=500.089). Calc.: molpeak(M+H)⁺: 500/502 Found: molpeak (M+H)⁺: 500/502. R_(f) value: 0.10(silica gel, DCM/MeOH/NH₃ 9:1:0.1).

EXAMPLE 4.46(R)-1-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-ethyl)-piperidin-3-ylamine

1.5 mL of a 5 N HCl solution in isopropanol are added to a solution of110 mg (0.21 mmol) tert-butyl[(R)-1-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-ethyl)-piperidin-3-yl]-carbaminate(Example 4.19) in 5 mL DCM and the reaction mixture is stirred for 4 hat RT. The precipitate formed is combined with a littletert-butylmethylether, filtered, washed with tert-butylmethylether anddried at 30° C.

Yield: 104 mg (99.5% of theory). C₂₆H₂₆ClN₃O.2HCl (M=504.892). Calc.:molpeak (M+H)⁺: 432/434 Found: molpeak (M+H)⁺: 432/434. R_(f) value:0.27 (silica gel, DCM/MeOH/NH₃ 9:1:0.1).

EXAMPLE 4.47[1-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-ethyl)-piperidin-4-ylmethyl]-methyl-amine

Prepared analogously to Example 4.46 from 160 mg (0.29 mmol) tert-butyl[1-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-ethyl)-piperidin-4-ylmethyl]-methyl-carbaminate(Example 4.18).

Yield: 156 mg (100% of theory). C₂₈H₃₀ClN₃O.2HCl (M=532.946). Calc.:molpeak (M+H)⁺: 460/462 Found: molpeak (M+H)⁺: 460/462. R_(f) value:0.13 (silica gel, DCM/MeOH/NH₃9:1:0.1).

EXAMPLE 4.481-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-ethyl)-pyrrolidin-3-ylamine

1 mL trifluoroacetic acid are added to a solution of 45 mg (0.09 mmol)tert-butyl[1-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-ethyl)-pyrrolidin-3-yl]-carbaminate(Example 4.15) in 5 mL DCM and the reaction mixture is stirred for 24 hat RT. The mixture is evaporated down i.vac., the residue is combinedwith 20 mL DCM, the organic phase is washed with saturated NaHCO₃solution and dried over Na₂SO₄. After the desiccant and solvent havebeen eliminated the desired product is obtained.

Yield: 15 mg (41.3% of theory). C₂₅H₂₄ClN₃O (M=417.943). Calc.: molpeak(M+H)⁺: 418/420 Found: molpeak (M+H)⁺: 418/420. HPLC retention time:5.86 min (method A).

EXAMPLE 4.49(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-ethyl)-methyl-piperidin-4-yl-amine

60 μL (0.8 mmol) trifluoroacetic acid are added to a solution of 22 mg(0.04 mmol) tert-butyl4-[(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-ethyl)-methyl-amino]-piperidin-1-carboxylatein 5 mL DCM and the reaction mixture is stirred for 24 h at RT. Themixture is evaporated down i.vac. and the residue is stirred withdiethyl ether. The precipitate is suction filtered, washed with diethylether and dried.

Yield: 12 mg (67.3% of theory). C₂₇H₂₈ClN₃O.CF₃COOH (M=560.017). Calc.:molpeak (M+H)⁺: 445/447 Found: molpeak (M+H)⁺: 445/447. R_(f) value:0.07 (silica gel, EtOAc/MeOH/NH₃ 80:20:2).

EXAMPLE 4.50 methyl1-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-ethyl)-pyrrolidine-2-carboxylate

0.15 mL ethyldiisopropylamine and 73 mg (0.44 mmol) proline-methyl ester(used as the hydrochloride) are added to a solution of 171 mg (0.4 mmol)2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-ethylmethanesulphonate in 2 mL DMF and the reaction mixture is stirred for 18h at RT. The mixture is evaporated down i.vac. and the residue ispurified by HPLC.

Yield: 10 mg (5.4% of theory). C₂₇H₂₅ClN₂O₃ (M=460.965). Calc.: molpeak(M+H)⁺: 461/463 Found: molpeak (M+H)⁺: 461/463. R_(f) value: 0.79(silica gel, cyc/EtOAc 1:1).

The following compounds may be prepared by the methods described:

Example R 4.51

4.52

4.53

4.54

4.55

4.56

4.57

EXAMPLE 4.58[1-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-ethyl)-piperidin-4-ylmethyl]-dimethyl-aminehydrochloride

Saturated ethereal HCl solution is added to a solution of 15 mg (0.03mmol)[1-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-ethyl)-piperidin-4-ylmethyl]-dimethyl-amine(Example 4.41) in 6 mL DCM and 4 mL acetone until no more precipitate isformed during the addition. The salt formed is suction filtered in anitrogen current and dried.

Yield: 10 mg (61.2% of theory). C₂₉H₃₂ClN₃O.HCl (M=510.512). Calc.:molpeak (M+H)⁺: 474/476 Found: molpeak (M+H)⁺: 474/476. Fp: >250° C.

EXAMPLE 55-(4-chloro-phenyl)-2-[3-methyl-4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridine

5a 2-(4-iodo-2-methyl-phenoxy)-ethanol

Under an N₂ atmosphere 2.34 g (10 mmol) 4-iodo-2-methyl-phenol are addedto a suspension batchwise, cooled to 0° C., of 0.48 g (11 mmol) NaH in50 mL THF and stirred for a further 30 min at this temperature. Then0.85 mL (12 mmol) 2-bromoethanol, dissolved in 5 mL THF, are addeddropwise and the mixture is stirred for 18 h at RT. 5 mL of DMF areadded and the reaction mixture is heated to 70° C. for 8 h. The mixtureis evaporated down i.vac., the residue is taken up in water, extractedexhaustively with EtOAc and dried with Na₂SO₄ After the desiccant andsolvent have been eliminated the residue is purified by chromatographyon silica gel (cyc/EtOAc 7:3).

Yield: 0.39 g (14.0% of theory). C₉H₁₁IO₂ (M=278.091). Calc.: molpeak(M+H)⁺: 279 Found: molpeak (M+H)⁺: 279. R_(f) value: 0.28 (silica gel,cyc/EtOAc 2:1).

5b2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxy}-ethanol

Prepared analogously to Example 4b from 380 mg (1.37 mmol)2-(4-iodo-2-methyl-phenoxy)-ethanol and 292 mg (1.37 mmol)5-(4-chloro-phenyl)-2-ethynyl-pyridine in 38 mL piperidine.

Yield: 340 mg (68.4% of theory). C₂₂H₁₈ClNO₂ (M=363.847). Calc.: molpeak(M+H)⁺: 364 Found: molpeak (M+H)⁺: 364. R_(f) value: 0.26 (silica gel,cyc/EtOAc 1:1).

5c2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxy}-ethylmethanesulphonate

Prepared analogously to Example 4.1a from 310 mg (0.93 mmol)2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxy}-ethanoland 88 μL (1.12 mmol) methanesulphonic acid chloride.

Yield: 300 mg (72.7% of theory). C₂₃H₂₀ClNO₄S (M=441.937). Calc.:molpeak (M+H)⁺: 442/444 Found: molpeak (M+H)⁺: 442/444. R_(f) value:0.35 (silica gel, cyc/EtOAc 1:1).

5d5-(4-chloro-phenyl)-2-[3-methyl-4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridine

A solution of 110 mg (0.25 mmol)2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxy}-ethylmethanesulphonate in 2.11 mL (25 mmol) pyrrolidine is heated to 70° C.for 3 h. The mixture is evaporated down i.vac., the residue is combinedwith water, extracted exhaustively with DCM and the organic phase isdried over Na₂SO₄. After the desiccant and solvent have been eliminatedand after recrystallisation from EtOH the desired product is obtained.

Yield: 55 mg (52.8% of theory). C₂₆H₂₅ClN₂O (M=416.955). Calc.: molpeak(M+H)⁺: 417/419 Found: molpeak (M+H)⁺: 417/419. HPLC retention time:7.19 min (method A).

EXAMPLE 5.15-(4-chloro-phenyl)-2-{4-[2-(2,5-dihydro-pyrrol-1-yl)-ethoxy]-3-methyl-phenylethynyl}-pyridine

Prepared analogously to Example 5d from 110 mg (0.25 mmol)2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxy}-ethylmethanesulphonate and 1.92 mL (25 mmol) 2,5-dihydro-1H-pyrrole.

Yield: 10 mg (9.6% of theory). C₂₆H₂₃ClN₂O (M=414.939). Calc.: molpeak(M+H)⁺: 415/417 Found: molpeak (M+H)⁺: 415/417. R_(f) value: 0.50(silica gel, EtOAc/MeOH/NH₃ 95:5:0.5).

EXAMPLE 5.25-(4-chloro-phenyl)-2-{4-[2-(4-isopropyl-piperidin-1-yl)-ethoxy]-3-methyl-phenylethynyl}-pyridine

164 mg (1.0 mmol) 4-isopropyl-piperidine (used as the hydrochloride) areadded to a solution of 88 mg (0.2 mmol)2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxy}-ethylmethanesulphonate and 0.34 mL (2 mmol) ethyldiisopropylamine in 1.8 mLDMF and the reaction mixture is stirred for 24 h at RT. It is filteredusing an injection filter and the reaction mixture is purified by HPLC.

Yield: 18 mg (19.4% of theory). C₃₀H₃₃ClN₂O (M=473.063). Calc.: molpeak(M+H)⁺: 473/475 Found: molpeak (M+H)⁺: 473/475. HPLC retention time:5.70 min (method B).

The following compounds are prepared as described in Example 5.2:

HPLC retention time empirical mass in min Example R Yield (%) formulaspectrum (method) 5.3

18.3 C₃₂H₂₉ClN₂O 493/495[M + H]⁺ 5.70 (B) 5.4

48.9 C₂₈H₃₀ClN₃O 460/462[M + H]⁺ 4.22 (B) 5.5

10.9 C₂₉H₃₁ClN₂O 459/461[M + H]⁺ 5.49 (B) 5.6

25.6 C₃₃H₃₁ClN₂O 507/509[M + H]⁺ 5.73 (B) 5.7

20.2 C₂₇H₂₅ClN₂O₂ 445/447[M + H]⁺ 4.82 (B) 5.8

24.6 C₂₇H₂₇ClN₂O₂ 447/449[M + H]⁺ 4.69 (B) 5.9

17.3 C₃₄H₃₃ClN₂O 521/523[M + H]⁺ 5.83 (B) 5.10

40.1 C₃₂H₃₁ClN₄O 523/525[M + H]⁺ 4.25 (B) 5.11

12.3 C₂₇H₂₇ClN₂O₂ 447/449[M + H]⁺ 4.89 (B) 5.12

31.0 C₂₆H₂₇ClN₂O₃ 451/453[M + H]⁺ 4.62 (B) 5.13

17.7 C₂₆H₂₃ClN₂O 415/417[M + H]⁺ 5.03 (B) 5.14

29.8 C₂₉H₃₁ClN₂O 459/461[M + H]⁺ 5.46 (B) 5.15

52.9 C₂₈H₃₀ClN₃O 460/462[M + H]⁺ 4.15 (B) 5.16

21.4 C₃₁H₃₄ClN₃O₃ 532/534[M + H]⁺ 5.43 (B) 5.17

19.8 C₂₉H₃₁ClN₂O 459/461[M + H]⁺ 5.43 (B) 5.18

28.1 C₂₈H₂₈ClN₃O₂ 474/476[M + H]⁺ 4.66 (B) 5.19

11.4 C₃₃H₃₈ClN₃O₃ 560/562[M + H]⁺ 5.60 (B) 5.20

7.4 C₂₈H₃₀ClN₃O₃S 524/526[M + H]⁺ 4.79 (B) 5.21

13.5 C₃₀H₃₁ClN₂O₃ 503/505[M + H]⁺ 5.16 (B) 5.22

14.0 C₃₂H₃₅ClN₂O₃ 531/533[M + H]⁺ 5.39 (B) 5.23

16.6 C₃₁H₃₆ClN₃O 502/504[M + H]⁺ 4.15 (B) 5.24

24.5 C₃₃H₄₀ClN₃O 530/532[M + H]⁺ 4.19 (B) 5.25

4.8 C₃₃H₃₈ClN₃O 528/530[M + H]⁺ 4.22 (B) 5.26

24.0 C₃₄H₃₁ClN₄O₂ 563/565[M + H]⁺ 4.92 (B) 5.27

36.8 C₃₅H₃₄ClN₃O₃S 612/614[M + H]⁺ 5.43 (B)

The following compounds are prepared as described in Example 5.2, whileafter the reaction has ended the reaction mixture is evaporated downi.vac., the residue is combined with water, the aqueous phase isexhaustively extracted with DCM and the organic phase is dried overNa₂SO₄. After the desiccant and solvent have been eliminated the residueis purified by chromatography on silica gel (DCM/MeOH 95:5 or 8:2).

HPLC retention time empirical mass in min Example R Yield (%) formulaspectrum (method) 5.28

37.6 C₂₉H₃₀ClN₃O 472/474[M + H]⁺ 4.05 (B) 5.29

35.8 C₃₂H₃₀ClN₃O₂ 524/526[M + H]⁺ 5.43 (B) 5.30

60.7 C₂₈H₂₉ClN₂O 446/448[M + H]⁺ 5.26 (B) 5.31

37.1 C₃₃H₃₁ClN₂O₂ 523/525[M + H]⁺ 5.33 (B) 5.32

53.2 C₂₉H₃₁ClN₂O 459/461[M + H]⁺ 5.53 (B) 5.33

48.8 C₂₈H₂₉ClN₂O 445/447[M + H]⁺ 5.26 (B) 5.34

46.1 C₃₀H₂₅ClN₂O 465/467[M + H]⁺ 5.33 (B)

The following compounds are prepared as described in Example 5.2, whilethe reaction mixture is heated to 60° C. for between 4 and 18 h asnecessary. After the reaction has ended the reaction mixture isevaporated down i.vac., the residue is combined with water, the aqueousphase is extracted exhaustively with DCM and the organic phase is driedover Na₂SO₄. After the desiccant and solvent have been eliminated theresidue is purified by chromatography on Alox.

empirical mass R_(f) value on Alox Example R Yield (%) formula spectrum(eluant) 5.35

64.7 C₂₆H₂₅ClN₂O₂ 433/435[M + H]⁺ 0.52(EtOAc) 5.36

74.8 C₂₈H₂₉ClN₂O₂ 461/463[M + H]⁺ 0.31(cyc/EtOAc 1:1) 5.37

48.5 C₂₆H₂₅ClN₂O₂ 433/435[M + H]⁺ 0.52(cyc/EtOAc 1:2) 5.38

78.1 C₂₈H₂₉ClN₂O₂ 461/463[M + H]⁺ 0.38(cyc/EtOAc 1:3) 5.39

65.3 C₂₇H₂₅ClN₂O 429/431[M + H]⁺ 0.70(cyc/EtOAc 2:1) 5.40

49.7 C₂₉H₂₉ClN₂O₂ 473/475[M + H]⁺ 0.34(cyc/EtOAc 1:1) 5.41

52.6 C₂₇H₂₇ClN₂O₂ 447/449[M + H]⁺ 0.21(cyc/EtOAc 1:1) 5.42

81.8 C₂₈H₂₆ClF₃N₂O₂ 499/501[M + H]⁺ 0.57(cyc/EtOAc 3:1) 5.43

47.0 C₂₇H₂₇ClN₂O 431/433[M + H]⁺ 0.72(cyc/EtOAc 2:1) 5.44

12.0 C₂₆H₂₅ClN₂O 417/419[M + H]⁺ 0.52(cyc/EtOAc 4:1) 5.45

32.6 C₂₇H₂₆ClN₃O₂ 461/463[M + H]⁺ 0.27(cyc/EtOAc 1:1) 5.46

44.3 C₂₈H₂₈ClN₃O₂ 474/476[M + H]⁺ 0.25(cyc/EtOAc 4:1)

The following compounds are prepared as described in Example 5.2, whilethe reaction mixture is heated to 60° C. for 18 h.

empirical mass R_(f) value on Alox Example R Yield (%) formula spectrum(eluant) 5.47

28.2 C₂₈H₂₉ClN₂O₂ 461/463[M + H]⁺ 0.40(cyc/EtOAc 1:1) 5.48

6.7 C₂₈H₃₁ClN₂O 447/449[M + H]⁺ 0.63(cyc/EtOAc 4:1)

The following compounds are prepared as described in Example 5.2,heating the reaction mixture to 60° C. for between 6 and 14 h asnecessary. After the reaction has ended the reaction mixture isevaporated down i.vac., the residue is combined with saturated K₂CO₃solution, the aqueous phase exhaustively extracted with DCM and theorganic phase is dried over Na₂SO₄. After the desiccant and solvent havebeen eliminated the residue is purified by chromatography on Alox.

R_(f) value on Alox (eluant) or HPLC retention time in empirical massmin Example R Yield (%) formula spectrum (method) 5.49

5.5 C₃₀H₂₉ClN₄O 497/499[M + H]⁺ 0.36(cyc/EtOAc 1:1) 5.50

8.3 C₃₂H₃₆ClN₃O 514/516[M + H]⁺ 4.12 (B) 5.51

3.9 C₃₀H₃₂ClN₃O 486/488[M + H]⁺ 4.46 (B) 5.52

36.2 C₃₀H₂₇ClN₂O₂ 483/485[M + H]⁺ 0.54(cyc/EtOAc 1:1)

The following compounds are prepared as described in Example 5.2,heating the reaction mixture to 100° C. for between 3 and 18 h asnecessary. After the reaction has ended the reaction mixture isevaporated down i.vac., the residue is combined with saturated K₂CO₃solution, the aqueous phase is exhaustively extracted with DCM and theorganic phase is dried over Na₂SO₄. After the desiccant and solvent havebeen eliminated the residue is purified by chromatography on Alox.

R_(f) value on Alox (eluant) or HPLC retention time in empirical massmin Example R Yield (%) formula spectrum (method) 5.53

75.7 C₃₀H₃₂ClN₃O₂ 502/504[M + H]⁺ 0.31(cyc/EtOAc 1:1) 5.54

23.3 C₃₂H₃₆ClN₃O 514/516[M + H]⁺ 4.22 (B) 5.55

15.2 C₂₉H₃₁ClN₂O 459/461[M + H]⁺ 5.39 (B)

EXAMPLE 5.561-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxy}-ethyl)-4-methyl-piperidin-4-ylamine

1 mL trifluoroacetic acid is added to a solution of 130 mg (0.23 mmol)tert butyl[1-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxy}-ethyl)-4-methyl-piperidin-4-yl]-carbaminate(Example 5.19) in 10 mL DCM and the reaction mixture is stirred for 14 hat RT. The mixture is evaporated down i.vac. (water bath temperaturemax. 30° C.), the residue is combined with dilute K₂CO₃ solution,extracted exhaustively with DCM and the organic phase is dried withNa₂SO₄. After the desiccant and solvent have been eliminated the residueis triturated with diisopropylether, the precipitate is suction filteredand dried in the air.

Yield: 65 mg (60.9% of theory). C₂₈H₃₀ClN₃O (M=460.024). Calc.: molpeak(M+H)⁺: 460/462 Found: molpeak (M+H)⁺: 460/462. HPLC retention time:4.09 min (method B).

The following compounds may be prepared by the processes described:

Example R 5.57

5.58

5.59

5.60

5.61

5.62

5.63

EXAMPLE 65-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-1-(2-pyrrolidin-1-yl-ethyl)-1H-indole

6a 2-(5-iodo-indol-1-yl)-ethanol

Under an N₂ atmosphere 30 g (121 mmol) 5-iodoindole are added to asuspension of 27.1 g (484 mmol) KOH in 150 mL DMSO. The reaction mixtureis kept for 1 h at RT, cooled to 0° C. with ice water, 9.7 mL (145 mmol)of 2-chloroethanol in 30 mL DMSO are slowly added dropwise and stirredfor 4.5 h at RT. The reaction mixture is combined with 1 L EtOAc, washedfour times with in each case 800 mL water and once with 400 mL saturatedNaCl solution and the organic phase is dried over Na₂SO₄. After thedesiccant and solvent have been eliminated the residue is purified bychromatography (silica gel, cyc/EtOAc 3:1).

Yield: 20.5 g (59.1% of theory). C₁₀H₁₀INO (M=287.102). Calc.: molpeak(M+H)⁺: 288 Found: molpeak (M+H)⁺: 288. HPLC retention time: 7.98 min(method A).

6b 2-(5-trimethylsilanylethynyl-indol-1-yl)-ethanol

398 mg (2.1 mmol) CuI and 1.47 g (2.1 mmol) Pd(PPh₃)₂Cl₂ are added to asolution, cooled to 0° C., of 30 g (104 mmol)2-(5-iodo-indol-1-yl)-ethanol and 18 mL (125 mmol)ethynyl-trimethyl-silane in 480 mL triethylamine and 120 mL THF andstirred for 30 min at 0° C. and 2 h at RT. The mixture is evaporateddown i.vac., the residue is taken up in 300 mL EtOAc, the organic phaseis washed with 150 mL water and dried over Na₂SO₄. After the desiccantand solvent have been eliminated the residue is purified bychromatography (silica gel, gradient: cyc/EtOAc 4:1 to 2:1).

Yield: 26.85 g (100% of theory). C₁₅H₁₉NOSi (M=257.411). Calc.: molpeak(M+H)⁺: 258 Found: molpeak (M+H)⁺: 258. R_(f) value: 0.25 (silica gel,cyc/EtOAc 2:1).

6c 2-(5-ethynyl-indol-1-yl)-ethanol

Under an N₂ atmosphere 29 g (91.8 mmol) TBAF are added to a solution of21.5 g (83.5 mmol) 2-(5-trimethylsilanylethynyl-indol-1-yl)-ethanol in500 mL THF and the reaction mixture is stirred for 1.5 h at RT. Themixture is evaporated down i.vac., the residue is taken up in 300 mLEtOAc, the organic phase is washed twice with in each case 200 mL waterand once with 200 mL saturated NaCl solution and dried over Na₂SO₄.After the desiccant and solvent have been eliminated the desired productis obtained in the form of a brown oil.

Yield: 15.46 g (100% of theory). C₁₂H₁₇NO (M=185.228). Calc.: molpeak(M+H)⁺: 186 Found: molpeak (M+H)⁺: 186. HPLC retention time: 7.04 min(method A).

6d 2-[5-(5-bromo-pyridin-2-ylethynyl)-indol-1-yl]-ethanol

Under an N₂ atmosphere 29.4 g (124 mmol) 2,5-dibromo-pyridine, 241 mg(1.3 mmol) CuI and 888 mg (1.3 mmol) Pd(PPh₃)₂Cl₂ are added to asolution of 23.0 g (124 mmol) 2-(5-ethynyl-indol-1-yl)-ethanol and 35 mL(248 mmol) diisopropylamine in 1150 mL THF and the reaction mixture isheated to 50° C. for 3.5 h. Another 241 mg CuI and 888 mg Pd(PPh₃)₂ Cl₂and 9 g (38 mmol) 2,5-dibromo-pyridine are added, the mixture is stirredfor a further 2.5 h at 50° C., 64 h at RT and a further 8 h at 60° C.The mixture is evaporated down i.vac., the residue is combined with 500mL 30% NH₃ solution and 800 mL EtOAc. The precipitate formed is filteredoff, washed with water and dried at 50° C. The two phases of thefiltrate are separated and the organic phase is evaporated down i.vac.The residue is stirred vigorously with 500 mL PE/diisopropylether (1:1)and suction filtered. The two product fractions are then combined.

Yield: 24.96 g (58.9% of theory). C₁₇H₁₃BrN₂O (M=341.210). Calc.:molpeak (M+H)⁺: 340/342 Found: molpeak (M+H)⁺: 340/342. R_(f) value:0.39 (silica gel, cyc/EtOAc 1:1).

6e 2-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-indol-1-yl}-ethanol

Under an N₂ atmosphere 56 mL 2 M Na₂CO₃ solution and 1.29 g (1.1 mmol)tetrakis-triphenylphosphane-palladium are added to a solution of 19.0 g(55.7 mmol) 2-[5-(5-bromo-pyridin-2-ylethynyl)-indol-1-yl]-ethanol and11.55 g (72.4 mmol) 4-chlorophenyl-boric acid in 320 mL 1,4-dioxane and80 mL MeOH and the reaction mixture is heated to 110° C. for 16 h. Themixture is evaporated down i.vac., the residue is combined with 300 mLwater and the suspension is stirred vigorously. The precipitate isfiltered off and washed with 200 mL water. The precipitate is suspendedthree times, each time with 600 mL PE/DCM (5:1), suction filtered andfinally dried in the air until a constant weight is obtained.

Yield: 17.11 g (82.4% of theory). C₂₃H₁₇ClN₂O (M=372.858). Calc.:molpeak (M+H)⁺: 373/375 Found: molpeak (M+H)⁺: 373/375. R_(f) value:0.42 (silica gel, DCM/MeOH/NH₃ 19:1:0.1).

6f 2-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-indol-1-yl}-ethylmethanesulphonate

Under an argon atmosphere 7.1 mL (51.5 mmol) triethylamine are added toa solution of 16.0 g (42.9 mmol)2-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-indol-1-yl}-ethanol in480 mL THF and 30 mL pyridine and this is cooled to 0° C. Then asolution of 4 mL (51.5 mmol) methanesulphonic acid chloride in 20 mL THFis slowly added dropwise, the mixture is allowed to warm up to RT andstirred for a further 2 h at RT. The reaction solution is filtered andevaporated down i.vac. The residue is combined with 1 L DCM, washed with400 mL water and the organic phase is dried over Na₂SO₄. After thedesiccant and solvent have been eliminated the residue is suspended with600 mL PE/DCM (5:1), suction filtered and finally dried in the air untila constant weight is obtained.

Yield: 17.10 g (88.4% of theory). C₂₄H₁₉ClN₂O₃S (M=450.948). Calc.:molpeak (M+H)⁺: 451/453 Found: molpeak (M+H)⁺: 451/453. R_(f) value: 0.9(silica gel, EtOAc/MeOH/NH₃ 19:1:0.1).

6g5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-1-(2-pyrrolidin-1-yl-ethyl)-1H-indole

1.1 mL (13.3 mmol) pyrrolidine are added to a solution of 600 mg (1.33mmol) 2-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-indol-1-yl}-ethylmethanesulphonate in 12 mL DMF and the reaction mixture is stirred for24 h at RT. The mixture is evaporated down i.vac., the residue is takenup in a little DCM and the product is purified by chromatography (silicagel, cyc/EtOAc 2:1)

Yield: 301 mg (53.1% of theory). C₂₇H₂₄ClN₃ (M=425.965). Calc.: molpeak(M+H)⁺: 426/428 Found: molpeak (M+H)⁺: 426/428. R_(f) value: 0.44(silica gel, cyc/EtOAc 2:1).

The following compounds are prepared as described in Example 6g, in eachcase using 5-20 eq. of the amine and stirring the reaction mixture for24 h at RT (method A) or for 24 h at RT and for 24 h at 60° C. (methodB) or for 7.5 h at 80° C. (method C) or for 48 h at 80° C. (method D).DCM and water are added, the phases are separated and the organic phaseis dried over Na₂SO₄. After the desiccant and solvent have beeneliminated the residue is purified by chromatography on Alox.

R_(f) value on Alox (eluant) or HPLC Example empirical mass retentiontime in min (method) R Yield (%) formula spectrum (method) 6.1(A)

33.1 C₂₇H₂₄ClN₃O 442/444[M + H]⁺ 0.24(DCM/MeOH/NH₃19:1:0.1) 6.2(B)

35.2 C₂₇H₂₄ClN₃O 442/444[M + H]⁺ 0.46(DCM/MeOH/NH₃9:1:0.1) 6.3(B)

34.7 C₂₈H₂₆ClN₃O 456/458[M + H]⁺ 0.32(DCM/MeOH/NH₃9:1:0.1) 6.4(B)

22.1 C₂₈H₂₆ClN₃ 440/442[M + H]⁺ 0.85(DCM/MeOH/NH₃9:1:0.1) 6.5(B)

26.3 C₂₈H₂₆ClN₃O 456/458[M + H]⁺ 0.42(DCM/MeOH/NH₃19:1:0.1) 6.6(B)

21.9 C₂₉H₂₈ClN₃O 470/472[M + H]⁺ 0.21(DCM/MeOH/NH₃19:1:0.1) 6.7(B)

27.0 C₂₉H₂₈ClN₃O 470/472[M + H]⁺ 0.07(DCM/MeOH/NH₃19:1:0.1) 6.8(B)

21.1 C₂₈H₂₆ClN₃O 456/458[M + H]⁺ 0.28(DCM/MeOH/NH₃19:1:0.1) 6.9(B)

17.2 C₂₉H₂₈ClN₃ 454/456[M + H]⁺ 0.33(DCM/MeOH/NH₃19:1:0.1)  6.10(C)

55.7 C₂₉H₂₈ClN₃ 454/456[M + H]⁺ 0.16(DCM/MeOH/NH₃19:1:0.1)  6.11(D)

11.6 C₃₀H₃₀ClN₃ 468/470[M + H]⁺ 0.18(DCM/MeOH/NH₃19:1:0.1)

EXAMPLE 6.12(2-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-indol-1-yl}-ethyl)-cyclopropylmethyl-propyl-amine

63 μL (0.44 mmol) cyclopropylmethyl-propyl-amine are added to a solutionof 100 mg (0.22 mmol)2-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-indol-1-yl}-ethylmethanesulphonate in 2 mL DMF and the reaction mixture is stirred for 16h at 60° C. The mixture is evaporated down i.vac., the residue is takenup in DCM, the organic phase is washed with water and dilute K₂CO₃solution and dried over Na₂SO₄. After the desiccant and solvent havebeen eliminated the residue is purified twice by chromatography (Alox,cyc/EtOAc 8:2 and cyc/DCM 1:1).

Yield 21 mg (20.2% of theory). C₃₀H₃₀ClN₃ (M=468.047). Calc.: molpeak(M+H)⁺: 468/470 Found: molpeak (M+H)⁺: 468/470. R_(f) value: 0.37 (Alox,cyc/EtOAc 8:2).

EXAMPLE 6.13(2-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-indol-1-yl}-ethyl)-cyclopropylmethyl-amine

0.46 mL (5.4 mmol) C-cyclopropyl-methylamine are added to a solution of2.03 g (4.5 mmol)2-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-indol-1-yl}-ethylmethanesulphonate in 20 mL DMF and the reaction mixture is stirred for 4h at 60° C. The mixture is evaporated down i.vac., the residue isstirred with DCM, the precipitate is suction filtered and dried in theair. The product is precipitated as the methanesulphonic acid salt.

Yield: 600 mg (25.5% of theory). C₂₇H₂₄ClN₃.CH₄O₃S (M=522.07). Calc.:molpeak (M+H)⁺: 426/428 Found: molpeak (M+H)⁺: 426/428. HPLC retentiontime: 5.23 min (method B).

EXAMPLE 6.14(2-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-indol-1-yl}-ethyl)-bis-cyclopropylmethyl-amine

36 μL (0.47 mmol) cyclopropanecarbaldehyde are added to a solution of100 mg (0.24 mmol)(2-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-indol-1-yl}-ethyl)-cyclopropylmethyl-aminein 20 mL MeOH at RT and 15 min later 59 mg (0.94 mmol) NaBH₄ and onedrop of glacial acetic acid are added. The mixture is stirred for 1 h atRT, evaporated down i.vac., the residue is taken up in dilute K₂CO₃solution, extracted exhaustively with EtOAc and dried over Na₂SO₄. Afterthe desiccant and solvent have been eliminated the residue is trituratedwith PE, suction filtered and dried.

Yield: 105 mg (93.1% of theory). C₃₁H₃₀ClN₃ (M=480.058). Calc.: molpeak(M+H)⁺: 480/482 Found: molpeak (M+H)⁺: 480/482. HPLC retention time:5.53 min (method B).

EXAMPLE 6.15(2-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-indol-1-yl}-ethyl)-cyclopropylmethyl-isobutyl-amine

Prepared analogously to Example 6.14; after the working up described,the crude product is purified by chromatography (Alox, cyc/EtOAc 4:1).

Yield: 35 mg (41.5% of theory). C₃₁H₃₂ClN₃ (M=482.074). Calc.: molpeak(M+H)⁺: 482/484 Found: molpeak (M+H)⁺: 482/484. R_(f) value: 0.83 (Alox,cyc/EtOAc 4:1). HPLC retention time: 5.7 min (method B).

EXAMPLE 6.16(2-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-indol-1-yl}-ethyl)-cyclopropylmethyl-prop-2-ynyl-amine

45 mg (0.33 mmol) K₂CO₃ and 13 μL (0.18 mmol) 3-bromo-propyne are addedat RT to a solution of 70 mg (0.16 mmol)(2-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-indol-1-yl}-ethyl)-cyclopropylmethyl-aminein 2 mL DMF and the reaction mixture is stirred for 4 h at RT. Themixture is evaporated down i.vac., the residue is taken up in water,extracted exhaustively with DCM and the organic phase is dried overNa₂SO₄. After the desiccant and solvent have been eliminated the residueis purified by chromatography (Alox, cyc/EtOAc 4:1).

Yield: 32 mg (42.1% of theory). C₃₀H₂₆ClN₃ (M=464.015). Calc.: molpeak(M+H)⁺: 464/466 Found: molpeak (M+H)⁺: 464/466. R_(f) value: 0.35 (Alox,cyc/EtOAc 4:1). HPLC retention time: 5.86 min (method B).

The following compounds may be prepared by the methods described inExamples 6.14 and 6.16:

HPLC retention time empirical mass in min Example R Yield (%) formulaspectrum (method) 6.17

6.18

6.19

30.1 C₃₀H₂₈ClN₃ 466/468[M + H]⁺ 5.5 (B) 6.20

6.21

EXAMPLE 71-{3-[5-(4-chloro-phenyl)-pyridin-2-yl]-prop-2-ynyl}-5-pyrrolidin-1-ylmethyl-1H-indole

7a 1-prop-2-ynyl-1H-indole-5-carbaldehyde

0.65 g (50% in mineral oil, 13.5 mmol) NaH are batchwise added to asolution, cooled to 0° C., of 2.0 g (13.5 mmol) 1H-indole-5-carbaldehydein 80 mL THF and after heating to RT stirred for 15 min. Then a solutionof 1.6 mL (80% in toluene, 15 mmol) propargyl bromide in 20 mL THF isslowly added dropwise and the reaction mixture is stirred overnight atRT. The mixture is evaporated down i.vac., the residue is combined withwater, the aqueous phase is exhaustively extracted with EtOAc and theorganic phase is dried over Na₂SO₄. After the desiccant and solvent havebeen eliminated the residue is purified by chromatography (silica gel,gradient: cyc/EtOAc 4:1 to 2:1).

Yield: 0.65 g (26.4% of theory). C₁₂H₉NO (M=183.212). Calc.: molpeak(M+H)⁺: 184 Found: molpeak (M+H)⁺: 184. R_(f) value: 0.34 (silica gel,cyc/EtOAc 3:1).

7b 1-prop-2-ynyl-5-pyrrolidin-1-ylmethyl-1H-indole

A solution of 250 mg (1.37 mmol) 1-prop-2-ynyl-1H-indole-5-carbaldehydeand 200 μL (2.37 mmol) pyrrolidine in 50 mL THF is adjusted to pH 5 withglacial acetic acid, combined with 550 mg (2.47 mmol) NaBH(OAc)₃ andstirred for 24 h at RT. 20 mL of saturated K₂CO₃ solution are added, themixture is extracted with 50 mL EtOAc and the organic phase is driedover Na₂SO₄. After the desiccant and solvent have been eliminated theresidue is purified by chromatography (silica gel, EtOAc/MeOH/NH₃95:5:0.5).

Yield: 325 mg (100% of theory). C₁₆H₁₈N₂ (M=238.335). Calc.: molpeak(M+H)⁺: 239 Found: molpeak (M+H)⁺: 239. R_(f) value: 0.38 (silica gel,EtOAc/MeOH/NH₃ 95:5:0.5).

7c1-[3-(5-bromo-pyridin-2-yl)-prop-2-ynyl]-5-pyrrolidin-1-ylmethyl-1H-indole

Under an argon atmosphere 5 mg (0.03 mmol) CuI and 18 mg (0.03 mmol)Pd(PPh₃)₂Cl₂ are added to a solution of 337 mg (1.41 mmol)1-prop-2-ynyl-5-pyrrolidin-1-ylmethyl-1H-indole and 345 mg (1.41 mmol)2,5-dibromo-pyridine in 50 mL THF and 0.4 mL diisopropylamine and thereaction mixture is stirred for 17 h at RT. The mixture is evaporateddown i.vac., the residue is taken up in 30 mL EtOAc, the organic phaseis washed with 30 mL water and 30 mL saturated NaCl solution and driedover Na₂SO₄. After the desiccant and solvent have been eliminated theresidue is purified by chromatography (silica gel, EtOAc/MeOH/NH₃95:5:0.5).

Yield: 145 mg (26.0% of theory). C₂₁H₂₀BrN₃ (M=394.318). Calc.: molpeak(M+H)⁺: 394/396 Found: molpeak (M+H)⁺: 394/396. R_(f) value: 0.62(silica gel, EtOAc/MeOH/NH₃ 90:10:1).

7d1-{3-[5-(4-chloro-phenyl)-pyridin-2-yl]-prop-2-ynyl}-5-pyrrolidin-1-ylmethyl-1H-indole

Under an argon atmosphere 0.5 mL 2 M Na₂CO₃ solution and 10 mg (0.01mmol) tetrakis-triphenylphosphane-palladium are added to a solution of59 mg (0.15 mmol)1-[3-(5-bromo-pyridin-2-yl)-prop-2-ynyl]-5-pyrrolidin-1-ylmethyl-1H-indoleand 50 mg (0.32 mmol) 4-chlorophenyl-boric acid in 5 mL 1,4-dioxane andthe reaction mixture is stirred for 2.5 h at 110° C. The mixture isevaporated down i.vac., the residue is combined with 3 mL water,extracted with 5 mL EtOAc, the organic phase is washed with saturatedNaCl solution and dried over Na₂SO₄. After the desiccant and solventhave been eliminated the residue is purified by HPLC.

Yield: 21.8 mg (34.1% of theory). C₂₇H₂₄ClN₃ (M=425.965). Calc.: molpeak(M+H)⁺: 426/428 Found: molpeak (M+H)⁺: 426/428. HPLC retention time:6.75 min (method A).

EXAMPLE 85-(4-chloro-phenyl)-2-[3-(4-pyrrolidin-1-ylmethyl-phenoxy)-prop-1-ynyl]-pyridine

8a 3-[5-(4-chloro-phenyl)-pyridin-2-yl]-prop-2-yn-1-ol

Under an N₂ atmosphere 1 mL (7.22 mmol) triethylamine, 23 mg (0.1 mmol)Pd(OAc)₂ and 57.5 mg (0.19 mmol) biphenyl-2-yl-di-tert-butyl-phosphaneare added to a solution of 500 mg (2.36 mmol)3-(5-bromo-pyridin-2-yl)-prop-2-yn-1-ol and 600 mg (3.72 mmol)4-chlorophenyl-boric acid in 10 mL DMF and 2.5 mL water and the reactionmixture is stirred for 8 h at 60° C. Then 400 mg (2.48 mmol)4-chlorophenyl-boric acid are added and the mixture is stirred for afurther 19 h at 60° C. The mixture is evaporated down i.vac., theresidue is combined with 10 mL water and 10 mL EtOAc, the aqueous phaseis saturated with NaCl, the organic phase is separated off and driedover Na₂SO₄. After the desiccant and solvent have been eliminated theresidue is purified by chromatography (silica gel, cyc/EtOAc₃ 2:1).

Yield: 228 mg (39.6% of theory). C₁₄H₁₀ClNO(M=243.695). Calc.: molpeak(M+H)⁺: 244/246 Found: molpeak (M+H)⁺: 244/246. R_(f) value: 0.23(silica gel, cyc/EtOAc 1:1).

8b5-(4-chloro-phenyl)-2-[3-(4-pyrrolidin-1-ylmethyl-phenoxy)-prop-1-ynyl]-pyridine

131 mg (0.5 mmol) triphenylphosphane are added to a solution of 100 mg(0.41 mmol) 3-[5-(4-chloro-phenyl)-pyridin-2-yl]-prop-2-yn-1-ol and 88mg (0.5 mmol) 4-pyrrolidin-1-ylmethyl-phenol in 4 mL THF. Then 0.1 mL(0.5 mmol) diisopropyl azo-dicarboxylate is slowly added dropwise andthe reaction mixture is stirred for 3 h at RT. The mixture is evaporateddown i.vac., the residue is taken up in 1 mL DMF and purified by HPLC.The product obtained, which still contains triphenylphosphane oxide, isagain purified by chromatography (silica gel, EtOAc after EtOAc/MeOH/NH₃9:1:0.1).

Yield: 6.5 mg (3.9% of theory). C₂₅H₂₃ClN₂O (M=402.928). Calc.: molpeak(M+H)⁺: 403/405 Found: molpeak (M+H)⁺: 403/405. R_(f) value: 0.72(silica gel, EtOAc/MeOH/NH₃ 9:1:0.1).

EXAMPLE 95-(4-chloro-phenyl)-2-[3-methyl-3-(4-pyrrolidin-1-ylmethyl-phenoxy)-but-1-ynyl]-pyridine

9a 4-(5-bromo-pyridin-2-yl)-2-methyl-but-3-yn-2-ol

Under an argon atmosphere 38 mg (0.2 mmol) CuI and 143 mg (0.2 mmol)Pd(PPh₃)₂Cl₂ are added to a solution of 0.99 mL (10.0 mmol)2-methyl-but-3-yn-2-ol and 2.44 g (10.0 mmol) 2,5-dibromo-pyridine in 50mL THF and 2.8 mL (20 mmol) diisopropylamine and the reaction mixture isstirred for 15 min at RT. The reaction mixture is combined with water,exhaustively extracted with EtOAc and the organic phase is dried overNa₂SO₄. After the desiccant and solvent have been eliminated the residueis purified by chromatography (silica gel, cyc/EtOAc 2:1).

Yield: 2.0 g (83.3% of theory). C₁₀H₁₀BrNO (M=240.101). Calc.: molpeak(M+H)⁺: 240/242 Found: molpeak (M+H)⁺: 240/242. R_(f) value: 0.29(silica gel, cyc/EtOAc 2:1).

9b 4-[5-(4-chloro-phenyl)-pyridin-2-yl]-2-methyl-but-3-yn-2-ol

Under an argon atmosphere 3 mL 2 M Na₂CO₃ solution and 173 mg (0.15mmol) tetrakis-triphenylphosphane-palladium are added to a solution of720 mg (3.0 mmol) 4-(5-bromo-pyridin-2-yl)-2-methyl-but-3-yn-2-ol and593 mg (3.6 mmol) 4-chlorophenyl-boric acid in 60 mL 1,4-dioxane and thereaction mixture is stirred for 18 h at 85° C. The mixture is evaporateddown i.vac., the residue is combined with water, extracted exhaustivelywith EtOAc, the organic phase is washed with water and dried overNa₂SO₄. After the desiccant and solvent have been eliminated the residueis purified by chromatography (silica gel, PE/EtOAc 1:1).

Yield: 420 mg (51.5% of theory). C₁₆H₁₄ClNO (M=271.749). Calc.: molpeak(M+H)⁺: 272/274 Found: molpeak (M+H)⁺: 272/274. R_(f) value: 0.42(silica gel, PE/EtOAc 1:1).

9c5-(4-chloro-phenyl)-2-[3-methyl-3-(4-pyrrolidin-1-ylmethyl-phenoxy)-but-1-ynyl]-pyridine

131 mg (0.5 mmol) triphenylphosphane are added to a solution of 136 mg(0.5 mmol) 4-[5-(4-chloro-phenyl)-pyridin-2-yl]-2-methyl-but-3-yn-2-oland 88 mg (0.5 mmol) 4-pyrrolidin-1-ylmethyl-phenol in 20 ml THF. Then0.1 mL (0.5 mmol) diisopropyl azo-dicarboxylate is slowly added dropwiseand the reaction mixture is stirred for 24 h at RT. The mixture isevaporated down i.vac., the residue is taken up in water, extractedexhaustively with EtOAc, the organic phase is washed with saturated NaClsolution and dried over Na₂SO₄. After the desiccant and solvent havebeen eliminated the residue is purified by HPLC.

Yield: 3 mg (1.4% of theory). C₂₇H₂₇ClN₂O (M=430.982). Calc.: molpeak(M+H)⁺: 431/433 Found: molpeak (M+H)⁺: 431/433. HPLC retention time:7.78 min (method A).

EXAMPLE 105-(4-chloro-phenyl)-2-[3-(4-pyrrolidin-1-ylmethyl-phenyl)-prop-2-ynyloxy]-pyridine

10a 5-(4-chloro-phenyl)-pyridin-2-ol

Under an N₂ atmosphere 21.7 mL 2 M Na₂CO₃ solution and 250 mg (0.22mmol) tetrakis-triphenylphosphane-palladium are added to a solution of8.0 g (21.7 mmol) 5-iodo-pyridin-2-ol and 3.81 g (23.9 mmol)4-chlorophenyl-boric acid in 120 mL 1,4-dioxane-and 30 mL dry-MeOH andthe reaction mixture is stirred for 19 h at 110° C. The mixture isevaporated down i.vac., the residue is combined with water, theprecipitate is filtered off, washed with water and dried at 40° C. inthe circulating air dryer until a constant weight is obtained.

Yield: 3.8 g (85.1% of theory). C₁₁H₈ClNO (M=205.646). Calc.: molpeak(M+H)⁺: 206/208 Found: molpeak (M+H)⁺: 206/208. R_(f) value: 0.56(silica gel, EtOAc/MeOH/NH₃ 9:1:0.1).

10b 5-(4-chloro-phenyl)-2-prop-2-ynyloxy-pyridine

2 mL (80% in toluene, 18.5 mmol) 3-bromo-propyne are added to asuspension of 3.8 g (18.5 mmol) 5-(4-chloro-phenyl)-pyridin-2-ol and 5.1g (37 mmol) K₂CO₃ in 50 mL DMF and the reaction mixture is stirred for64 h at RT. The mixture is evaporated down i.vac., the residue iscombined with 80 mL water, extracted with 150 mL EtOAc and the organicphase is dried over Na₂SO₄. After the desiccant and solvent have beeneliminated the residue is purified by chromatography (silica gel,cyc/EtOAc 2:1).

Yield: 216 mg (4.8% of theory). C₁₄H₁₀ClNO (M=243.695). Calc.: molpeak(M+H)⁺: 244/246 Found: molpeak (M+H)⁺: 244/246. R_(f) value: 0.16(silica gel, cyc/EtOAc 2:1).

10c5-(4-chloro-phenyl)-2-[3-(4-pyrrolidin-1-ylmethyl-phenyl)-prop-2-ynyloxy]-pyridine

Under an N₂ atmosphere 221 mg (0.68 mmol) Cs₂CO₃, 4 mg (0.02 mmol) CuIand 23 mg (0.02 mmol) tetrakis-triphenylphosphane-palladium are added toa solution of 110 mg (0.45 mmol)5-(4-chloro-phenyl)-2-prop-2-ynyloxy-pyridine and 129 mg (0.45 mmol)1-(4-iodo-benzyl)-pyrrolidine in 9 mL THF and the reaction mixture isstirred for 4.5 h at RT. The mixture is evaporated down i.vac., theresidue is combined with 20 mL 3% NH₃ solution and 40 mL EtOAc, theorganic phase is separated off and dried over Na₂SO₄. After thedesiccant and solvent have been eliminated the residue is purified firstby HPLC and then by chromatography (silica gel, DCM/MeOH/NH₃ 19:1:0.1).

Yield: 28 mg (15.5% of theory). C₂₅H₂₃ClN₂O (M=402.928). Calc.: molpeak(M+H)⁺: 403/405 Found: molpeak (M+H)⁺: 403/405. R_(f) value: 0.33(silica gel, DCM/MeOH/NH₃ 19:1:0.1). HPLC retention time: 6.43 min(method A).

EXAMPLE 111-(2-{4-[4-(4-chloro-phenyl)-thiophen-2-ylethynyl]-phenoxy}-ethyl)-pyrrolidine

11a (4-bromo-thiophen-2-ylethynyl)-trimethyl-silane

Under an argon atmosphere 0.37 g (1.94 mmol) CuI, 2.24 g (1.94 mmol)tetrakis-triphenylphosphane-palladium and 16.2 mL triethylamine areadded to a solution of 10.0 g (38.85 mmol) 2,4-dibromothiophene in 300mL THF, the reaction mixture is cooled to −78° C. and then at thistemperature a solution of 5.6 mL (38.85 mmol) ethynyl-trimethyl-silanein 250 mL THF is slowly added dropwise. After the addition has ended themixture is allowed to heat up slowly to RT and stirred overnight. Themixture is evaporated down i.vac., the residue is combined with water,extracted exhaustively with DCM and the combined organic phases aredried over MgSO₄. After the desiccant and solvent have been eliminatedthe residue is triturated with PE, filtered to remove insolubleingredients and the solvent is evaporated down. The residue is purifiedby chromatography (silica gel, PE).

Yield: 9.5 g (56.6% of theory). C₉H₁₁BrSSi (M=259.242). R_(f) value:0.77 (silica gel, PE).

11b 4-bromo-2-ethynyl-thiophene

4.6 g (14.58 mmol) TBAF are added to a solution, cooled to 0° C., of 6.3g (14.58 mmol) (4-bromo-thiophen-2-ylethynyl)-trimethyl-silane in 60 mLTHF. The cooling bath is removed and the mixture is stirred for afurther 30 min. The reaction mixture is combined with EtOAc, washed withwater and the organic phase is dried over MgSO₄. After the desiccant andsolvent have been eliminated the residue is purified by chromatography(silica gel, PE).

Yield: 1.9 g (69.7% of theory). C₆H₃BrS (M=187.059). Calc.: molpeak(M+H)⁺: 186/188 Found: molpeak (M+H)⁺: 186/188.

11c 1-{2-[4-(4-bromo-thiophen-2-ylethynyl)-phenoxy]-ethyl}-pyrrolidine

Under an argon atmosphere 0.3 mL (3.13 mmol) piperidine, 14.9 mg (0.08mmol) CuI and 90.3 mg (0.08 mmol) tetrakis-triphenylphosphane-palladiumare added to a solution of 293 mg (1.56 mmol)4-bromo-2-ethynyl-thiophene and 620 mg (1.56 mmol)1-[2-(4-iodo-phenoxy)-ethyl]-pyrrolidine in 10 mL THF and the reactionmixture is stirred overnight at RT. To complete the reaction another 150mg (0.8 mmol) 4-bromo-2-ethynyl-thiophene are added and the mixture isstirred for a further 24 h at RT. The mixture is evaporated down i.vac.,the residue is triturated with EtOAc and the insoluble ingredients arefiltered off. After the solvent has been eliminated the residue ispurified by chromatography (silica gel, EtOAc/MeOH/NH₃ 8:2:0.2).

Yield: 300 mg (51.0% of theory). C₁₈H₁₈BrNOS (M=376.318). Calc.: molpeak(M+H)⁺: 376/378 Found: molpeak (M+H)⁺: 376/378. R_(f) value: 0.52(silica gel, EtOAc/MeOH/NH₃ 9:1:0.1).

11d1-(2-{4-[4-(4-chloro-phenyl)-thiophen-2-ylethynyl]-phenoxy}-ethyl)-pyrrolidine

Under an N₂ atmosphere 5 mL 2 M Na₂CO₃ solution and 47 mg (0.41 mmol)tetrakis-triphenylphosphane-palladium are added to a solution of 310 mg(0.82 mmol)1-{2-[4-(4-bromo-thiophen-2-ylethynyl)-phenoxy]-ethyl}-pyrrolidine and129 mg (0.82 mmol) 4-chlorophenyl-boric acid in 10 mL 1,4-dioxane andthe reaction mixture is refluxed for 1 h. The hot solution is filteredthrough a fibreglass filter, the filtrate is extracted with EtOAc, theorganic phase is washed with water and dried over MgSO₄. After thedesiccant and solvent have been eliminated the residue is purified bychromatography (silica gel, EtOAc/MeOH/NH₃ 8:2:0.2).

Yield: 23 mg (6.8% of theory). C₂₄H₂₂ClNOS (M=407.966). Calc.: molpeak(M+H)⁺: 408/410 Found: molpeak (M+H)⁺: 408/410. HPLC retention time:5.35 min (method B).

EXAMPLE 122-(4-chloro-phenyl)-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyrazine

12a 5-(4-chloro-phenyl)-pyrazin-2-ylamine

Under an argon atmosphere 50 mL 2 M Na₂CO₃ solution and 1.2 g (1.0 mmol)tetrakis-triphenylphosphane-palladium are added to a solution of 8.7 g(50.0 mmol) 5-bromo-pyrazin-2-ylamine and 8.0 g (50.0 mmol)4-chlorophenyl-boric acid in 150 mL 1,4-dioxane and 50 mL MeOH and thereaction mixture is heated to 110° C. for 2.5 h. The mixture isevaporated down i.vac., the residue is combined with water, extractedexhaustively with EtOAc and the organic phase is dried over Na₂SO₄.After the desiccant and solvent have been eliminated the residue ispurified by chromatography (silica gel, gradient: DCM to DCM/MeOH 20:1).

Yield: 8.3 g (80.7% of theory). C₁₀H₈ClN₃ (M=205.648). Calc.: molpeak(M+H)⁺: 206/208 Found: molpeak (M+H)⁺: 206/208. HPLC retention time:7.15 min (method A).

12b 2-(4-chloro-phenyl)-5-iodo-pyrazine

With the exclusion of light, 4.9 mL (40.0 mmol) tert-butylnitrite and7.6 g (30 mmol) iodine are added to a solution of 4.8 g (23.3 mmol)5-(4-chloro-phenyl)-pyrazin-2-ylamine in 100 mL CCl₄ and 50 mL DCM andthe reaction mixture is stirred overnight at RT. It is combined with 100mL water and 50 mL 10% Na₂S₂O₃ solution, the organic phase is separatedoff, washed again with 50 mL 10% Na₂S₂O₃ solution and twice with 50 mLwater and dried over MgSO₄. It is filtered through activated charcoal,evaporated down i.vac. and the residue is purified by chromatography(silica gel, gradient: PE to PE/EtOAc 8:2).

Yield: 3.4 g (46.0% of theory). C₁₀H₆ClIN₂ (M=316.530). Calc.: molpeak(M+H)⁺: 317/319 Found: molpeak (M+H)⁺: 317/319. R_(f) value: 0.55(silica gel, PE/EtOAc 9:1).

12c2-(4-chloro-phenyl)-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyrazine

Under an N₂ atmosphere 19 mg (0.1 mmol) CuI, 82 mg (0.1 mmol)[1,1′-bis-(diphenylphosphine)-ferrocene]-palladium(II)-chloride areadded to a solution of 316 mg (1.0 mmol)2-(4-chloro-phenyl)-5-iodo-pyrazine and 215 mg (1.0 mmol)1-[2-(4-ethynyl-phenoxy)-ethyl]-pyrrolidine in 50 mL THF and 0.4 mL (3mmol) triethylamine and the reaction mixture is stirred overnight at RT.To complete the reaction another 100 mg (0.32 mmol)2-(4-chloro-phenyl)-5-iodo-pyrazine are added and the mixture is againstirred overnight. It is evaporated down i.vac., the residue is combinedwith 10% Na₂CO₃ solution, extracted exhaustively with DCM, the combinedorganic phases are washed three times with water and dried over MgSO₄.This is filtered through activated charcoal, evaporated down i.vac. andthe residue is purified by chromatography (silica gel, gradient: EtOActo EtOAc/MeOH/NH₃ 9:9:1).

Yield: 170 mg (42.1% of theory). C₂₄H₂₂ClN₃O (M=403.915). Calc.: molpeak(M+H)⁺: 404/406 Found: molpeak (M+H)⁺: 404/406. R_(f) value: 0.58(silica gel, DCM/MeOH/NH₃ 9:1:0.1).

EXAMPLE 132-(4-chloro-phenyl)-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridine

13a 5-bromo-2-(4-chloro-phenyl)-pyridine

Under an N₂ atmosphere 11 mL 2 M Na₂CO₃ solution and 240 mg (0.21 mmol)tetrakis-triphenylphosphane-palladium are added to a solution of 3.00 g(10.6 mmol) 5-bromo-2-iodo-pyridine and 3.37 g (21.1 mmol)4-chlorophenyl-boric acid in 60 mL 1,4-dioxane and 15 mL MeOH and thereaction mixture is heated to 110° C. for 3 h. The mixture is evaporateddown i.vac., the residue is combined with 50 mL water, 10 mL 3% NH₃solution and 150 mL EtOAc, the organic phase is separated off and driedover Na₂SO₄. After the desiccant and solvent have been eliminated theresidue is purified by chromatography (silica gel, cyc).

Yield: 1.52 g (53.6% of theory). C₁₁H₇BrClN (M=268.542) Calc.: molpeak(M+H)⁺: 268/270/272 Found: molpeak (M+H)⁺: 268/270/272. R_(f) value: 0.1(silica gel, cyc).

13b2-(4-chloro-phenyl)-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridine

Under an N₂ atmosphere 773 mg (2.25 mmol) Cs₂CO₃, 14 mg (0.08 mmol) CuIand 87 mg (0.08 mmol) tetrakis-triphenylphosphane-palladium are added toa solution of 403 mg (1.5 mmol) 5-bromo-2-(4-chloro-phenyl)-pyridine and322 mg (1.5 mmol) 1-[2-(4-ethynyl-phenoxy)-ethyl]-pyrrolidine in 10 mLTHF and the reaction mixture is stirred for 4 h at RT. Then it is heatedto 60° C. for 16 h. The mixture is evaporated down i.vac., the residueis combined with 30 mL water, 5 mL 3% NH₃ solution and 60 mL EtOAc, theorganic phase is separated off and dried over Na₂SO₄. After thedesiccant and solvent have been eliminated the residue is purified firstby chromatography (silica gel, EtOAc/MeOH/NH₃ 19:1:0.1) and then byHPLC.

Yield: 9 mg (2.2% of theory). C₂₅H₂₃ClN₂O (M=402.928). Calc.: molpeak(M+H)⁺: 403/405 Found: molpeak (M+H)⁺: 403/405. HPLC retention time:8.11 min (method A).

EXAMPLE 14 ethyl5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-3-methyl-1-(2-pyrrolidin-1-yl-ethyl)-1H-indole-2-carboxylate

14a ethyl3-methyl-1-(2-pyrrolidin-1-yl-ethyl)-5-trimethylsilanylethynyl-1H-indole-2-carboxylate

Under an argon atmosphere 577 mg (0.5 mmol)tetrakis-triphenylphosphane-palladium and 95 mg (0.5 mmol) CuI are addedto a solution of 2.82 g (10 mmol) ethyl5-bromo-3-methyl-1H-indole-2-carboxylate and 1.52 mL (11 mmol)ethynyl-trimethyl-silane in 3 mL (30 mmol) piperidine and 30 mL THF andthe reaction mixture is stirred for 14 h at 60° C. It is diluted withwater, extracted exhaustively with EtOAc, the combined organic phasesare washed with saturated NaCl solution and dried over Na₂SO₄. After thedesiccant and solvent have been eliminated the residue is purified bychromatography (silica gel, cyc/EtOAc 9:1).

Yield: 1.3 g (43.4% of theory). C₁₇H₂₁NO₂Si (M=299.448). Calc.: molpeak(M+H)⁺: 300 Found: molpeak (M+H)⁺: 300. R_(f) value: 0.61 (silica gel,cyc/EtOAc 7:3).

14b ethyl5-ethynyl-3-methyl-1-(2-pyrrolidin-1-yl-ethyl)-1H-indole-2-carboxylate

Under an argon atmosphere 562 mg (3.3 mmol)1-(2-chloro-ethyl)-pyrrolidine (used as the hydrochloride) are added toa suspension of 900 mg (3.0 mmol) ethyl3-methyl-1-(2-pyrrolidin-1-yl-ethyl)-5-trimethylsilanylethynyl-1H-indole-2-carboxylateand 457 mg (3.3 mmol) K₂CO₃ in 10 mL DMF and the reaction mixture isstirred for 42 h at 60° C. It is diluted with water, extractedexhaustively with EtOAc, the combined organic phases are washed withwater and dried over Na₂SO₄. After the desiccant and solvent have beeneliminated the residue is purified by chromatography (silica gel,EtOAc/MeOH/NH₃ 90:10:1).

Yield: 250 mg (25.6% of theory). C₂₀H₂₄N₂O₂ (M=324.426). Calc.: molpeak(M+H)⁺: 325 Found: molpeak (M+H)⁺: 325. HPLC retention time: 4.59 min(method B).

14c ethyl5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-3-methyl-1-(2-pyrrolidin-1-yl-ethyl)-1H-indole-2-carboxylate

Under an argon atmosphere 11 mg (0.02 mmol) Pd(PPh₃)₂Cl₂ and 3 mg (0.02mmol) CuI are added to a solution of 250 mg (0.77 mmol) ethyl5-ethynyl-3-methyl-1-(2-pyrrolidin-1-yl-ethyl)-1H-indole-2-carboxylateand 243 mg (0.77 mmol) 5-(4-chloro-phenyl)-2-iodo-pyridine in 1.52 mL(15.4 mmol) piperidine and 25 mL THF and the reaction mixture is stirredfor 4 h at RT. It is diluted with water, extracted exhaustively withEtOAc, the combined organic phases are washed with water and saturatedNaCl solution and dried over Na₂SO₄. After the desiccant and solventhave been eliminated the residue is purified first by chromatography(silica gel, cyc/EtOAc 2:1) and then by HPLC.

Yield: 7 mg (1.8% of theory). C₃₁H₃₀ClN₃O₂ (M=512.057). Calc.: molpeak(M+H)⁺: 512/514 Found: molpeak (M+H)⁺: 512/514. R_(f) value: 0.67 (Alox,cyc/EtOAc 2:1). HPLC retention time: 5.96 min (method B).

EXAMPLE 15N-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-3-methyl-pyridin-2-y1}-2-pyrrolidin-1-yl-acetamide

15a N-(5-bromo-3-methyl-pyridin-2-yl)-2-chloro-acetamide

1.75 mL (22 mmol) chloroacetyl chloride are added to a solution, cooledto 0° C., of 3.74 g (20 mmol) 2-amino-5-bromo-3-methylpyridine in 50 mLDCM and then 6.1 mL (44 mmol) triethylamine are slowly added dropwise.After the addition has ended the ice bath is removed and the reactionmixture is stirred for 4 h at RT. It is poured onto water, extractedexhaustively with DCM, the combined organic phases are washed with waterand saturated NaCl solution and dried over Na₂SO₄. After the desiccantand solvent have been eliminated the residue is purified bychromatography (silica gel, cyc/EtOAc 2:1).

Yield: 2.7 g (51.2% of theory). C₈H₈BrClN₂O (M=263.523). Calc.: molpeak(M+H)⁺: 263/265/267 Found: molpeak (M+H)⁺: 263/265/267. R_(f) value:0.48 (silica gel, cyc/EtOAc 1:1).

15b N-(5-bromo-3-methyl-pyridin-2-yl)-2-pyrrolidin-1-yl-acetamide

0.81 mL (9.9 mmol) pyrrolidine are added to a suspension of 2.37 g (9.0mmol) N-(5-bromo-3-methyl-pyridin-2-yl)-2-chloro-acetamide and 2.49 g(18 mmol) K₂CO₃ in 22.5 mL DMF and the reaction mixture is stirred for20 h at RT. It is diluted with water, extracted exhaustively with EtOAc,the combined organic phases are washed with water and dried over Na₂SO₄.After the desiccant and solvent have been eliminated the residue istaken up in a little diisopropylether, cooled to 0° C., the crystalsprecipitated are suction filtered and dried in the air.

Yield: 1.4 g (52.2% of theory). C₁₂H₁₆BrN₃O (M=298.185). Calc.: molpeak(M+H)⁺: 298/300 Found: molpeak (M+H)⁺: 298/300. R_(f) value: 0.48(silica gel, EtOAc/MeOH/NH₃ 90:10:1).

15cN-(3-methyl-5-trimethylsilanylethynyl-pyridin-2-yl)-2-pyrrolidin-1-yl-acetamide

Under an argon atmosphere 35 mg (0.03 mmol)tetrakis-triphenylphosphane-palladium and 5.7 mg (0.03 mmol) CuI areadded to a solution of 447 mg (1.5 mmol)N-(5-bromo-3-methyl-pyridin-2-yl)-2-pyrrolidin-1-yl-acetamide and 0.23mL (1.65 mmol) ethynyl-trimethyl-silane in 0.45 mL (4.5 mmol) piperidineand 10 mL THF and the reaction mixture is stirred for 14 h at RT. Tocomplete the reaction a further 35 mgtetrakis-triphenylphosphane-palladium are added and the reaction mixtureis heated to 50° C. for 4 h. It is diluted with water, extractedexhaustively with EtOAc, the combined organic phases are washed withsaturated NaCl solution and dried over Na₂SO₄. After the desiccant andsolvent have been eliminated the residue is purified by chromatography(silica gel, EtOAc/MeOH/NH₃ 90:10:1).

Yield: 210 mg (44.4% of theory). C₁₇H₂₅N₃OSi (M=315.494). Calc.: molpeak(M+H)⁺: 316 Found: molpeak (M+H)⁺: 316. R_(f) value: 0.65 (silica gel,EtOAc/MeOH/NH₃ 90:10:1).

15d N-(5-ethynyl-3-methyl-pyridin-2-yl)-2-pyrrolidin-1-yl-acetamide

Under an argon atmosphere 132 mg (0.48 mmol) TBAF are added to asolution of 150 mg (0.48 mmol)N-(3-methyl-5-trimethylsilanylethynyl-pyridin-2-yl)-2-pyrrolidin-1-yl-acetamidein 10 mL THF and the reaction mixture is stirred overnight at RT. Themixture is evaporated down i.vac., the residue is taken up in EtOAc, theorganic phase is washed with water and saturated NaCl solution and driedover Na₂SO₄. After the desiccant and solvent have been eliminated thedesired product is obtained.

Yield: 110 mg (95.2% of theory). C₁₄H₁₇N₃O (M=243.311). Calc.: molpeak(M+H)⁺: 244 Found: molpeak (M+H)⁺: 244. R_(f) value: 0.48 (silica gel,EtOAc/MeOH/NH₃ 90:10:1).

15eN-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-3-methyl-pyridin-2-yl}-2-pyrrolidin-1-yl-acetamide

Under an argon atmosphere 4 mg (0.01 mmol) Pd(PPh₃)₂Cl₂ and 1 mg (0.01mmol) CuI are added to a solution of 73 mg (0.3 mmol)N-(5-ethynyl-3-methyl-pyridin-2-yl)-2-pyrrolidin-1-yl-acetamide and 95mg (0.3 mmol) 5-(4-chloro-phenyl)-2-iodo-pyridine in 59 μL (0.6 mmol)piperidine and 10 mL THF and the reaction mixture is stirred for 30 minat RT. It is evaporated down i.vac., the residue is taken up in EtOAc,the organic phase is washed with water and saturated NaCl solution anddried over Na₂SO₄. After the desiccant and solvent have been eliminatedthe residue is purified first by chromatography (silica gel,EtOAc/MeOH/NH₃ 95:5:0.5) and then by HPLC.

Yield: 22 mg (17.0% of theory). C₂₅H₂₃ClN₄O (M=430.941). Calc.: molpeak(M+H)⁺: 431/433 Found: molpeak (M+H)⁺: 431/433. R_(f) value: 0.39(silica gel, EtOAc/MeOH/NH₃ 90:10:1).

EXAMPLE 16{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-3-methyl-pyridin-2-yl}-(2-pyrrolidin-1-yl-ethyl)-amine

16a (5-bromo-3-methyl-pyridin-2-yl)-(2-pyrrolidin-1-yl-ethyl)-amine

Under an argon atmosphere 2 mL of a 1 M solution of LiAlH₄ in THF areslowly added dropwise to a solution, cooled to 0° C., of 800 mg (2.68mmol) N-(5-bromo-3-methyl-pyridin-2-yl)-2-pyrrolidin-1-yl-acetamide(Example 15b) in 10 mL THF and the reaction mixture is stirred for 3 hat this temperature. 20% NaOH is slowly added dropwise, solid K₂CO₃ isadded to the suspension and this is stirred vigorously. The precipitateis filtered off, the filtrate is evaporated down and the residue ispurified by chromatography (silica gel, EtOAc/MeOH/NH₃ 80:20:2).

Yield: 500 mg (65.6% of theory). C₁₂H₁₈BrN₃ (M=284.201). Calc.: molpeak(M+H)⁺: 284/286 Found: molpeak (M+H)⁺: 284/286. R_(f) value: 0.25(silica gel, EtOAc/MeOH/NH₃ 80:20:2).

16b(3-methyl-5-trimethylsilanylethynyl-pyridin-2-yl)-(2-pyrrolidin-1-yl-ethyl)-amine

Prepared analogously to Example 15c from 500 mg (1.76 mmol)(5-bromo-3-methyl-pyridin-2-yl)-(2-pyrrolidin-1-yl-ethyl)-amine and 0.29mL (2.11 mmol) ethynyl-trimethyl-silane, while the reaction mixture isheated to 50° C. for 12 h.

Yield: 400 mg (75.4% of theory). C₁₇H₂₇N₃Si (M=301.511). Calc.: molpeak(M+H)⁺: 302 Found: molpeak (M+H)⁺: 302. R_(f) value: 0.27 (silica gel,EtOAc/MeOH/NH₃ 90:10:1).

16c (5-ethynyl-3-methyl-pyridin-2-yl)-(2-pyrrolidin-1-yl-ethyl)-amine

Prepared analogously to Example 15d from 400 mg (1.33 mmol)(3-methyl-5-trimethylsilanyl-ethynyl-pyridin-2-yl)-(2-pyrrolidin-1-yl-ethyl)-amine.

Yield: 250 mg (82.2% of theory). C₁₄H₁₉N₃ (M=229.328). R_(f) value: 0.51(silica gel, EtOAc/MeOH/NH₃ 80:20:2).

16d{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-3-methyl-pyridin-2-yl}-(2-pyrrolidin-1-yl-ethyl)-amine

Prepared analogously to Example 15e from 69 mg (0.3 mmol)(5-ethynyl-3-methyl-pyridin-2-yl)-(2-pyrrolidin-1-yl-ethyl)-amine and 95mg (0.3 mmol) 5-(4-chloro-phenyl)-2-iodo-pyridine, while after workingup the crude product is purified by chromatography on Alox (cyc/EtOAc6:4).

Yield: 12 mg (9.6% of theory). C₂₅H₂₅ClN₄ (M=416.958). Calc.: molpeak(M+H)⁺: 417/419 Found: molpeak (M+H)⁺: 417/419. R_(f) value: 0.42 (Alox,cyc/EtOAc 1:1).

EXAMPLE 176-(4-chloro-phenyl)-2-(4-pyrrolidin-1-ylmethyl-phenylethynyl)-quinoline

17a (E)-3-ethoxy-acrylic acid chloride

20 g (0.172 mol) (E)-3-ethoxy-acrylic acid are added batchwise to asolution of 14.99 mL (0.206 mol) thionyl chloride in 300 ml of tolueneat RT and heated to 90° C. for 2 h. The reaction mixture is evaporatedto dryness and the yellow oil remaining is further reacted without anymore purification.

17b (E)-N-(4-bromo-phenyl)-3-ethoxy-acrylamide

26.63 g (0.155 mol) of 4-bromoaniline are dissolved in 120 ml ofpyridine and 23.14 g (0.172 mol) (E)-3-ethoxy-acrylic acid chloride areadded dropwise at a temperature between 0° C. and 5° C. and the mixtureis stirred for one hour at 0° C. Then the reaction mixture is allowed towarm up to RT and stirred for 14 h. The reaction mixture is combinedwith water, the precipitate formed is filtered off and washed withwater. The solid is dried at 65° C. in the drying cupboard.

Yield: 37.84 g (90.4% of theory). C₁₁H₁₂BrNO₂ (M=270.12). Calc.: molpeak(M+H)⁺: 270/272 Found: molpeak (M+H)⁺: 270/272. R_(f) value: 0.7 (silicagel, cyc/EtOAc 1:1).

17c 6-bromo-1H-quinolin-2-one

37.8 g (0.14 mol) (E)-N-(4-bromo-phenyl)-3-ethoxy-acrylamide are addedbatchwise to 200 mL concentrated sulphuric acid and stirred for 2 h atRT. Then the reaction mixture is poured into ice water, the precipitateis filtered off and washed with water. The solid is dried at 70° C. inthe drying cupboard.

Yield: 28.6 g (91.2% of theory). C₉H₆BrNO (M=224.05). Calc.: molpeak(M+H)⁺: 224/226 Found: molpeak (M+H)⁺: 224/226. R_(f) value: 0.6 (silicagel, EtOAc).

17d 6-(4-chloro-phenyl)-1H-quinolin-2-one

A solution of 22.7 g (0.101 mol) 6-bromo-1H-quinolin-2-one in 380 mL1,4-dioxane and 380 mL MeOH is combined with 141.5 ml (0.283 ml) 2 MNa₂CO₃ solution and saturated with argon. Then 3.735 g (3.23 mmol)tetrakis-triphenyl-phosphane-palladium and 4-chlorophenylboric acid areadded successively. The reaction mixture is heated to 110° C. for fourhours and then evaporated down to a volume of 300 mL. 1.2 L water areadded and the precipitate is filtered off. The solid is dried at 55° C.in the drying cupboard, washed with diisopropylether and dried again.

Yield: 25.4 (89.5% of theory). C₁₅H₁₀ClNO (M=255.70). Calc.: molpeak(M+H)⁺: 256/258 Found: molpeak (M+H)⁺: 256/258. R_(f) value: 0.6 (silicagel, EtOAc/PE 3:1).

17e 2-bromo-6-(4-chloro-phenyl)-quinoline

50 g (0.174 mol) phosphorus oxybromide are heated to 65° C., combinedwith 10 g (0.039 mol) 6-(4-chloro-phenyl)-1H-quinolin-2-one and heatedto 110° C. for 3 h. The reaction mixture is then poured onto ice waterand made alkaline with ammonia solution. The precipitate is filtered offand dried in the drying cupboard at 60° C.

Yield: 12.28 g (98.8% of theory). C₁₅H₉BrClN (M=318.60). Calc.: molpeak(M+H)⁺: 318/320/322 Found: molpeak (M+H)⁺: 318/320/322. R_(f) value: 0.8(silica gel, cyc/EtOAc 3:1).

17f 4-[6-(4-chloro-phenyl)-quinolin-2-ylethynyl]-benzaldehyde

Under a nitrogen atmosphere 0.6 mg CuI, 9.3 mg Pd(PPh₃)₂Cl₂ and 318 mg(1 mmol) 2-bromo-6-(4-chloro-phenyl)-quinoline are added successively toa solution of 85 mg (0.66 mmol) 4-ethynyl-benzaldehyde and 2.6 mL (18.67mmol) triethylamine in 5 mL absolute DMF and 10 mL acetonitrile. Thereaction mixture is stirred for 14 hours at RT and evaporated down. Thepurification is carried out by column chromatography on silica gel(PE/EtOAc 1:1).

Yield: 290 mg (78.8% of theory). C₂₄H₁₄ClNO (M=367.83). Calc.: molpeak(M+H)⁺: 368/370 Found: molpeak (M+H)⁺: 368/370. R_(f) value: 0.84(silica gel, DCM/MeOH/NH₃ 90:10:1).

17g6-(4-chloro-phenyl)-2-(4-pyrrolidin-1-ylmethyl-phenylethynyl)-quinoline,

3 mg p-toluenesulphonic -acid and 100 μL glacial acetic acid are addedto a solution of 290 mg (0.78 mmol)4-[6-(4-chloro-phenyl)-quinoline-2-ylethynyl]-benzaldehyde and 56 mg(0.78 mmol) pyrrolidine in 10 mL THF at RT and stirred for 30 minutes.Then 334 mg (1.57 mmol) NaBH(OAc)₃ are added batchwise and the reactionmixture is stirred for 14 h. A few drops of water are added dropwise tothe reaction mixture and this is stirred for 15 minutes. The reactionmixture is then combined with K₂CO₃ and filtered. The filtrate isevaporated down. The purification is carried out by columnchromatography on silica gel (DCM/MeOH/NH₃ 90:10:1).

Yield: 150 mg (45% of theory). melting point: 170-193° C. C₂₈H₂₃ClN₂(M=422.96). Calc.: molpeak (M+H)⁺: 423/425 Found: molpeak (M+H)⁺:423/425. R_(f) value: 0.49 (silica gel, DCM/MeOH/NH₃ 90:10:1).

The following compounds are prepared analogously to Example 17g with 17fas educt:

mass Example R empirical formula spectrum mp [° C.] R_(f) value 17.1

C₂₉H₂₆ClN₃ 452/54[M + H]⁺ 176-182 0.33 17.2

C₂₈H₂₃ClN₂O 439/41[M + H]⁺ 170-174 0.45 17.3

C₃₀H₂₇ClN₂O 467/69[M + H]⁺ 159-165 0.52 17.4

C₃₂H₃₀ClN₃ 492/94[M + H]⁺ 140-148 0.21 17.5

C₃₀H₂₇ClN₂O 467/69[M + H]⁺ 139-147 0.61 17.6

C₃₀H₂₇ClN₂O 467/69[M + H]⁺ 143-173 0.61 17.7

C₃₁H₂₈ClN₃O 494/96[M + H]⁺ 142-145 0.31 17.8

C₃₀H₂₆ClN₃O 480/82[M + H]⁺ 165-170 0.30 17.9

C₂₉H₂₄ClN₃O 466/68[M + H]⁺ 152-157 0.45 17.10

C₃₃H₂₇ClN₄ 515/17[M + H]⁺ 214-219 0.47 17.11

C₂₈H₂₅ClN₂O 441/43[M + H]⁺ 153 0.38 17.12

C₃₀H₂₇ClN₂O 467/69[M + H]⁺ 130-136 0.32 17.13

C₃₁H₂₄ClN₃  474/476[M + H]⁺ 140-149 0.43 17.14

C₃₀H₂₇ClN₂O 467/69[M + H]⁺ 190-192 0.30 17.15

C₂₈H₂₃ClN₂OS 471/73[M + H]⁺ 170-174 0.38 17.16

C₂₈H₂₃ClN₂O₂S 487/89[M + H]⁺ 216-220 0.61 17.17

C₃₅H₂₉ClN₂O 529/31[M + H]⁺ 208-219 0.34

The R_(f) values specified are obtained on silica gel with DCM/MeOH/NH₃90:10:1 as the mobile phase.

EXAMPLE 186-(4-chloro-phenyl)-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-quinoline

18a 1-[2-(4-iodo-phenoxy)-ethyl]-pyrrolidine

A reaction mixture of 44 g (0.2 mol) 4-iodophenol, 34 g (0.2 mol)1-(2-chloro-ethyl)-pyrrolidine-hydrochloride, 110.56 g (0.8 mol) K₂CO₃and 800 mL DMF is stirred for 48 h at RT. The reaction mixture isfiltered and the filtrate is evaporated down. The residue is taken up inwater and extracted with EtOAc. The organic phase is extracted withsaturated NaCl solution and dried over Na₂SO₄. The purification iscarried out by column chromatography on silica gel (EtOAc/MeOH/NH₃85:15:1.5).

Yield: 34.8 g (54.9% of theory). C₁₂H₁₆INO (M=317.17). R_(f) value: 0.49(silica gel, EtOAc/MeOH/NH₃ 90:10:1).

18b 1-[2-(4-trimethylsilanylethynyl-phenoxy)-ethyl]-pyrrolidine

Under a nitrogen atmosphere and while cooling with ice a reactionmixture of 1.5 g (4.72 mmol) 1-[2-(4-iodo-phenoxy)-ethyl]-pyrrolidine,0.735 ml (5.2 mmol) ethynyl-trimethyl-silane, 15 mL piperidine, 115.5 mg(0.1 mmol) tetrakis-triphenylphosphane-palladium and 19 mg (0.1 mmol)CuI is stirred for 1 h. Then the reaction mixture is evaporated down,the residue is taken up in 20 mL water and extracted with EtOAc. Theorganic phase is dried over Na₂SO₄. The purification is carried out bycolumn chromatography on silica gel (EtOAc/MeOH/NH₃ 95:5:0.5).

Yield: 1.244 g (91.5% of theory). C₁₇H₂₅NOSi (M=287.48) Calc.: molpeak(M+H)⁺: 288 Found: molpeak (M+H)⁺: 288. R_(f) value: 0.45 (silica gel,EtOAc/MeOH/NH₃ 90:10:1)

18c 1-[2-(4-ethynyl-phenoxy)-ethyl]-pyrrolidine

A reaction mixture of 1.22 g (4.24 mmol)1-[2-(4-trimethylsilanylethynyl-phenoxy)-ethyl]-pyrrolidine, 1.47 g(4.67 mmol) TBAF and 25 mL THF is stirred for 3 h at RT. Then thereaction mixture is evaporated down and the residue is combined with 20mL saturated NaCl solution and 50 mL EtOAc. The organic phase is driedover Na₂SO₄. The purification is carried out by column chromatography onsilica gel (EtOAc/MeOH/NH₃ 90:10:1).

Yield: 0.91 g (100% of theory). C₁₄H₁₇NO (M=215.29). Calc.: molpeak(M+H)⁺: 216 Found: molpeak (M+H)⁺: 216. R_(f) value: 0.33 (silica gel,EtOAc/MeOH/NH₃ 90:10:1).

18d6-(4-chloro-phenyl)-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-quinoline

In a nitrogen atmosphere, 0.6 mg CuI, 9.3 mg Pd(PPh₃)₂Cl₂ and 318 mg (1mmol) 2-bromo-6-(4-chloro-phenyl)-quinoline are added successively to asolution of 142 mg (0.66 mmol)1-[2-(4-ethynyl-phenoxy)-ethyl]-pyrrolidine and 2.6 mL (18.67 mmol)triethylamine in 5 mL absolute DMF and 10 mL acetonitrile. The reactionmixture is stirred for 14 h at RT and evaporated down. The purificationis carried out by column chromatography on silica gel (DCM/MeOH/NH₃90:10:1).

Yield: 148 mg (32.7% of theory). melting point: 176-185° C. C₂₉H₂₅ClN₂O(M=452.98). Calc.: molpeak (M+H)⁺: 453/455 Found: molpeak (M+H)⁺:453/455. R_(f) value: 0.71 (silica gel, DCM/MeOH/NH₃ 80:20:1).

EXAMPLE 196-(4-chloro-phenyl)-2-[3-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-quinoline

19a 1-[2-(3-ethynyl-phenoxy)-ethyl]-pyrrolidine

Prepared analogously to Example 18a from1-(2-chloro-ethyl)-pyrrolidine-hydrochloride and 3-ethynyl-phenol.

Yield: 1.44 g (79% of theory). C₁₄H₁₇NO (M=215.29). Calc.: molpeak(M+H)⁺: 216 Found: molpeak (M+H)⁺: 216. R_(f) value: 0.37 (silica gel,DCM/MeOH/NH₃ 90:10:1).

19b6-(4-chloro-phenyl)-2-[3-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-quinoline

Prepared analogously to Example 18d from1-[2-(3-ethynyl-phenoxy)-ethyl]-pyrrolidine and2-bromo-6-(4-chloro-phenyl)-quinoline.

Yield: 135 mg (29.8% of theory). melting point: 114-117° C. C₂₉H₂₅ClN₂O(M=452.98). Calc.: molpeak (M+H)⁺: 453/455 Found: molpeak (M+H)⁺:453/455. R_(f) value: 0.61 (silica gel, DCM/MeOH/NH₃ 80:20:1).

EXAMPLE 206-(4-chloro-phenyl)-2-(2-pyrrolidin-1-ylmethyl-benzoxazol-5-ylethynyl)-quinoline

20a 5-bromo-2-chloromethyl-benzoxazole

1.79 mL (13.3 mmol) 2-chloro-1,1,1-trimethoxy-ethane are added dropwiseat RT to a solution of 2.5 g (13.29 mmol) 2-amino-4-bromophenol in 20 mLethanol and stirred for 48 h. Then 0.4 mL2-chloro-1,1,1-trimethoxy-ethane are added and stirred for 20 h. Thereaction mixture is evaporated down. The purification is carried out bycolumn chromatography on silica gel (DCM/ethanol 80:1).

Yield: 2 g (60.9% of theory). C₈H₅BrClNO (M=246.49). Calc.: molpeak(M+H)⁺: 246/248/250 Found: molpeak (M+H)⁺: 246/248/250. R_(f) value:0.95 (silica gel, DCM/ethanol 20:1).

20b 5-bromo-2-pyrrolidin-1-ylmethyl-benzoxazole

A solution of 2 g (8.11 mmol) 5-bromo-2-chloromethyl-benzoxazole in 30mL DMF is combined with 2.24 g (16.22 mmol) K₂CO₃ and 0.9 mL (10.78mmol) pyrrolidine and stirred for 24 hours at RT. The reaction mixtureis diluted with water and extracted with EtOAc. The organic phase isdried over Na₂SO₄, the desiccant is filtered off and the filtrate isevaporated down.

Yield: 2.2 g (96.4% of theory). C₁₂H₁₃BrN₂O (M=281.15). Calc.: molpeak(M+H)⁺: 281/283 Found: molpeak (M+H)⁺: 281/283. R_(f) value: 0.15(silica gel, DCM/ethanol 50:1).

20c 5-iodo-2-pyrrolidin-1-ylmethyl-benzoxazole

71 mg (0.36 mmol) CuI, 1 g (3.55 mmol)5-bromo-2-pyrrolidin-1-ylmethyl-benzoxazole and 1.07 g (7.15 mmol) NaIare successively placed in a flask in an argon atmosphere. Then 0.08 mL(0.73 mmol) N,N′-dimethylethylenediamine and 3.5 mL 1,4-dioxane areadded and the reaction mixture is refluxed for 14 h. The reactionmixture is then combined with 20 mL concentrated ammonia solution at RT,diluted with 100 mL water and extracted with DCM. The organic phase isextracted three times with water and dried over Na₂SO₄.

Yield: 1 g (72.8% of theory). C₁₂H₁₃IN₂O (M=328.15). Calc.: molpeak(M+H)⁺: 329 Found: molpeak (M+H)⁺: 329. R_(f) value: 0.35 (silica gel,cyc/EtOAc 1:1).

20d 2-pyrrolidin-1-ylmethyl-5-trimethylsilanylethynyl-benzoxazole

Prepared analogously to Example 18b from5-iodo-2-pyrrolidin-1-ylmethyl-benzoxazole and ethynyl-trimethyl-silane.

Yield: 0.5 g (91.6% of theory). C₁₇H₂₂N₂OSi (M=298.46). Calc.: molpeak(M+H)⁺: 299 Found: molpeak (M+H)⁺: 299. R_(f) value: 0.5 (silica gel,DCM/MeOH/NH₃ 90:10:1).

20e 5-ethynyl-2-pyrrolidin-1-ylmethyl-benzoxazole

Prepared analogously to Example 18c from2-pyrrolidin-1-ylmethyl-5-trimethylsilanylethynyl-benzoxazole.

Yield: 0.265 g (69.9% of theory). C₁₄H₁₄N₂O (M=226.28). Calc.: molpeak(M+H)⁺: 227 Found: molpeak (M+H)⁺: 227. R_(f) value: 0.79 (silica gel,DCM/MeOH/NH₃ 80:20:1).

20f6-(4-chloro-phenyl)-2-(2-pyrrolidin-1-ylmethyl-benzoxazol-5-ylethynyl)-quinoline

Prepared analogously to Example 18d from5-ethynyl-2-pyrrolidin-1-ylmethyl-benzoxazole and2-bromo-6-(4-chloro-phenyl)-quinoline.

Yield: 90 mg (13.9% of theory). melting point: 151-153° C. C₂₉H₂₂ClN₃O(M=463.97). Calc.: molpeak (M+H)⁺: 464/466 Found: molpeak (M+H)⁺:464/466. R_(f) value: 0.53 (silica gel, DCM/MeOH/NH₃ 90:10:1).

EXAMPLE 215-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-pyrrolidin-1-ylmethyl-benzoxazole

A reaction mixture of 260 mg (0.792 mmol)5-iodo-2-pyrrolidin-1-ylmethyl-benzoxazole, 171 mg (0.8 mmol)5-(4-chloro-phenyl)-2-ethynyl-pyridine, 23 mg (0.02 mmol)tetrakis-triphenylphosphane-palladium, 3.8 mg (0,02 mmol) CuI and 350 mg(1.075 mmol) Cs₂CO₃ in 10 mL THF is stirred for 14 h in an argonatmosphere at RT. Then the reaction mixture is evaporated down and theresidue is purified by column chromatography on silica gel (DCM/MeOH80:1).

Yield: 140 mg (42.7% of theory). melting point: 145° C. C₂₅H₂₀ClN₃O(M=413.91). Calc.: molpeak (M+H)⁺: 414/416 Found: molpeak (M+H)⁺:414/416. R_(f) value: 0.1 (silica gel, DCM/MeOH 50:1).

EXAMPLE 225-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-(2-pyrrolidin-1-yl-ethoxy)-benzoicacid

1.6 mL aqueous 1 M NaOH are added to a solution of 369 mg (0.8 mmol)methyl5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-(2-pyrrolidin-1-yl-ethoxy)-benzoate(Example 3.4) in 20 mL MeOH and the reaction mixture is heated to 70° C.for 3 h. It is combined with 1.6 mL 1 M HCl, evaporated down i.vac. andthe residue is coevaporated twice with in each case 20 mL MeOH. Theresidue is triturated with EtOH with heating and suction filtered.

Yield: 340 mg (95.1% of theory). C₂₆H₂₃ClN₂O₃ (M=446.938). Calc.:molpeak (M+H)⁺: 447/449 Found: molpeak (M+H)⁺: 447/449. HPLC retentiontime: 7.0 min (method A).

EXAMPLE 22.15-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-N-methyl-2-(2-pyrrolidin-1-yl-ethoxy)-benzamide

80 mg (0.25 mmol) TBTU and 69 μL triethylamine are added to a solutionof 112 mg (0.25 mmol)5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-(2-pyrrolidin-1-yl-ethoxy)-benzoicacid (Example 22) in 5 mL DMF and the reaction mixture is stirred for 2h at RT. Then 31 mg (1.0 mmol) methylamine are added and stirring iscontinued for a further 2 h at RT. The mixture is evaporated downi.vac., the residue is combined with dilute Na₂CO₃ solution, extractedexhaustively with DCM and the organic phase is dried over Na₂SO₄. Afterthe desiccant and solvent have been eliminated the residue is purifiedby chromatography (silica gel, DCM to DCM/MeOH/NH₃ 7:3:0.3).

Yield: 45 mg (39.1% of theory). C₂₇H₂₆ClN₃O₂ (M=459.980). Calc.: molpeak(M+H)⁺: 460/462 Found: molpeak (M+H)⁺: 460/462. HPLC retention time: 6.8min (method A).

The following compounds are prepared as described in Example 22.1, whilein Example 22.5 ammonium carbonate is used as the ammonia source:

HPLC retention time empirical mass in min Example R Yield (%) formulaspectrum (method) 22.2

42.2 C₂₈H₂₈ClN₃O₂ 474/476[M + H]⁺ 6.95 (A) 22.3

9.3 C₃₂H₃₅ClN₄O₂ 543/545[M + H]⁺ 5.30 (A) 22.4

6.9 C₂₉H₂₈ClN₃O₂ 486/488[M + H]⁺ 7.07 (A) 22.5

4.0 C₂₆H₂₄ClN₃O₂ 446/448[M + H]⁺ 6.10 (A)

EXAMPLE 235-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-(2-pyrrolidin-1-yl-ethoxy)-phenylamine

200 mg (2.5 mmol) NaHCO₃ and 300 mg (1.1 mmol) tin-(II)-chloridedihydrate are added to a solution of 100 mg (0.22 mmol)5-(4-chloro-phenyl)-2-[3-nitro-4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridine(Example 3.13) in 10 mL EtOAc and the reaction mixture is refluxed for 2h. To complete the reaction a further 200 mg (2.5 mmol) NaHCO₃, 300 mg(1.1 mmol) tin-(II)-chloride dihydrate and 1 mL MeOH are added and themixture is refluxed for a further 2 h. After cooling, 4 g of silica gelare added, the solvent is eliminated i.vac. and the residue is purifiedby chromatography (silica gel, DCM/MeOH/NH₃ 8:2:0.2).

Yield: 85 mg (39.1% of theory). C₂₅H₂₄ClN₃O (M=417.943). Calc.: molpeak(M+H)⁺: 418/420 Found: molpeak (M+H)⁺: 418/420. HPLC retention time: 7.1min (method A).

EXAMPLE 23.1N-[5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-acetamide

16 μL (170 μmol) acetic anhydride are added to a solution of 35 mg (84μmol)5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-(2-pyrrolidin-1-yl-ethoxy)-phenylaminein 2 mL DCM and the reaction mixture is stirred overnight at RT and thenpurified by chromatography on silica gel (gradient: EtOAc toEtOAc/MeOH/NH₃ 7:3:0.3) without any further working up

Yield: 10 mg (26.0% of theory). C₂₇H₂₆ClN₃O₂ (M=459.980). Calc.: molpeak(M+H)⁺: 460/462 Found: molpeak (M+H)⁺: 460/462. R_(f) value: 0.55(silica gel, DCM/MeOH/NH₃ 90:10:1).

EXAMPLE 23.2N-[5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-methanesulphonamide

Under an N₂ atmosphere 39 μL (0.5 mmol) methanesulphonic acid chlorideare added to a solution of 100 mg (0.24 mmol)5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-(2-pyrrolidin-1-yl-ethoxy)-phenylamineand 161 μL (2 mmol) pyridine in 10 mL DCM and the reaction mixture isstirred for 2 h at RT. To complete the reaction a further 160 μLpyridine and 39 μL methanesulphonic acid chloride are added and themixture is stirred overnight. It is combined with 10% Na₂CO₃ solution,the organic phase is separated off and the solvent is eliminated i.vac.The residue is purified by HPLC.

Yield: 15 mg (13.0% of theory). C₂₆H₂₆ClN₃O₃S (M=496.032). Calc.:molpeak (M+H)⁺: 496/498 Found: molpeak (M+H)⁺: 496/498. HPLC retentiontime: 6.8 min (method A).

EXAMPLE 23.3[5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-dimethyl-amine

180 μL (2.4 mmol) formalin solution (37% in water), 63 mg (1.0 mmol)NaBH₃CN and 57 μL (1.0 mmol) acetic acid are added to a solution of 100mg (0.24 mmol)5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-(2-pyrrolidin-1-yl-ethoxy)-phenylaminein 5 mL acetonitrile and the reaction mixture is stirred overnight atRT. It is acidified with 12% HCl, stirred vigorously for one hour,combined with saturated Na₂CO₃ solution until an alkaline reaction isobtained and extracted exhaustively with DCM. After elimination of thesolvent the residue is purified by HPLC.

Yield: 9 mg (8.4% of theory). C₂₇H₂₈ClN₃O (M=445.997). Calc.: molpeak(M+H)⁺: 446/448 Found: molpeak (M+H)⁺: 446/448. HPLC retention time: 6.7min (method A).

EXAMPLE 23.4[5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-methyl-amine

Under a nitrogen atmosphere 178 μL (1.35 mmol) N,N-dimethylformamidedimethylacetal are added to a solution of 100 mg (0.24 mmol)5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-(2-pyrrolidin-1-yl-ethoxy)-phenylaminein 2 mL DMF, the reaction mixture is stirred for 5 h at 60° C. andcooled to RT overnight. Then 32 mg (0.85 mmol) NaBH₄ are added and themixture is again heated to 60° C. for 1 h. To complete the reaction afurther 32 mg NaBH₄ are added and the mixture is heated to 60° C. for afurther 4 h. After cooling it is combined with saturated NaHCO₃solution, exhaustively extracted with EtOAc and the organic phase isdried over MgSO₄. After the desiccant and solvent have been eliminatedthe residue is purified by HPLC.

Yield: 0.5 mg (0.5% of theory). C₂₆H₂₆ClN₃O (M=431.970). Calc.: molpeak(M+H)⁺: 432/434 Found: molpeak (M+H)⁺: 432/434. HPLC retention time: 7.5min (method A).

The following compounds may also be obtained by the processes describedin the foregoing experimental section:

Example R 24.1

24.2

24.3

24.4

24.5

24.6

24.7

24.8

24.9

24.10

24.11

24.12

24.13

24.14

24.15

24.16

24.17

The following compounds may also be obtained by the processes describedin the foregoing experimental section:

Example R 25.1

25.2

25.3

25.4

25.5

25.6

25.7

25.8

25.9

25.10

25.11

25.12

25.13

25.14

25.15

25.16

25.17

The following compounds may also be obtained by the processes describedin the foregoing experimental section:

Example R 26.1

26.2

26.3

26.4

26.5

26.6

26.7

26.8

26.9

26.10

26.11

26.12

26.13

26.14

26.15

26.16

26.17

The following compounds may also be obtained by the processes describedin the foregoing experimental section:

Example R 27.1

27.2

27.3

27.4

27.5

27.6

27.7

27.8

27.9

27.10

27.11

27.12

27.13

27.14

27.15

27.16

27.17

The following compounds may also be obtained by the processes describedin the foregoing experimental section:

Example R 28.1

28.2

28.3

28.4

28.5

28.6

28.7

28.8

28.9

28.10

28.11

28.12

28.13

28.14

28.15

28.16

28.17

The following compounds may also be obtained by the processes describedin the foregoing experimental section:

Example R 29.1

29.2

29.3

29.4

29.5

29.6

29.7

29.8

29.9

29.10

29.11

28.12

29.13

29.14

29.15

The following compounds may also be obtained by the processes describedin the foregoing experimental section:

Example R 30.1

30.2

30.3

30.4

30.5

30.6

30.7

30.8

30.9

30.10

30.11

30.12

30.13

30.14

30.15

30.16

30.17

The following compounds may also be obtained by the processes describedin the foregoing experimental section:

Example R 31.1

31.2

31.3

31.4

31.5

31.6

31.7

31.8

31.9

31.10

31.11

31.12

31.13

31.14

31.15

31.16

31.17

The compounds of Examples 32 to 32.12 may also be obtained by theprocesses described in the foregoing experimental section:

EXAMPLE 32

EXAMPLE 32.1

EXAMPLE 32.2

EXAMPLE 32.3

EXAMPLE 32.4

EXAMPLE 32.5

EXAMPLE 32.6

EXAMPLE 32.7

EXAMPLE 32.8

EXAMPLE 32.9

EXAMPLE 32.10

EXAMPLE 32.11

EXAMPLE 32.12

The following compounds may also be obtained by the processes describedin the foregoing experimental section:

Example R 33.1

33.2

33.3

33.4

33.5

33.6

33.7

33.8

33.9

33.10

33.11

33.12

33.13

33.14

Some test methods for determining an MCH-receptor antagonistic activitywill now be described. In addition, other test methods known to theskilled man are used, e.g. by inhibiting the MCH-receptor-mediatedinhibition of cAMP production, as described by Hoogduijn M et al. in“Melanin-concentrating hormone and its receptor are expressed andfunctional in human skin”, Biochem. Biophys. Res Commun. 296 (2002)698-701 and by biosensory measurement of the binding of MCH to the MCHreceptor in the presence of antagonistic substances by plasmonresonance, as described by Karlsson O P and Lofas S. in “Flow-MediatedOn-Surface Reconstitution of G-Protein Coupled Receptors forApplications in Surface Plasmon Resonance Biosensors”, Anal. Biochem.300 (2002), 132-138. Other methods of testing antagonistic activity toMCH receptors are contained in the references and patent documentsmentioned hereinbefore, and the description of the test methods used ishereby incorporated in this application.

MCH-1 receptor binding test Method: MCH binding to hMCH-1R transfectedcells Species: Human Test cell: hMCH-1R stably transfected intoCHO/Galpha16 cells Results: IC50 values

Membranes from CHO/Galpha16 cells stably transfected with human hMCH-1Rare resuspended using a syringe (needle 0.6×25 mm) and diluted in testbuffer (50 mM HEPES, 10 mM MgCl₂, 2 mM EGTA, pH 7.00; 0.1% bovine serumalbumin (protease-free), 0.021% bacitracin, 1 μg/ml aprotinin, 1 μg/mlleupeptin and 1 μM phosphoramidone) to a concentration of 5 to 15 μg/ml.200 microlitres of this membrane fraction (contains 1 to 3 μg ofprotein) are incubated for 60 minutes at ambient temperature with 100 pMof ¹²⁵I-tyrosyl melanin concentrating hormone (¹²⁵I-MCH commerciallyobtainable from NEN) and increasing concentrations of the test compoundin a final volume of 250 microlitres. After the incubation the reactionis filtered using a cell harvester through 0.5% PEI treated glass fibrefilters (GF/B, Unifilter Packard). The membrane-bound radioactivityretained on the filter is then determined after the addition ofscintillator substance (Packard Microscint 20) in a measuring device(TopCount of Packard).

The non-specific binding is defined as bound radioactivity in thepresence of 1 micromolar MCH during the incubation period.

The analysis of the concentration binding curve is carried out on theassumption of one receptor binding site.

Standard:

Non-labelled MCH competes with labelled ¹²⁵I-MCH for the receptorbinding with an IC₅₀ value of between 0.06 and 0.15 nM.

The KD value of the radioligand is 0.156 nM.

MCH-1 Receptor-coupled Ca²⁺ Mobilisation Test

-   Method: Calcium mobilisation test with human MCH (FLIPR³⁸⁴)-   Species: Human-   Test cells: CHO/Galpha 16 cells stably transfected with hMCH-R1-   Results:    -   1st measurement: % stimulation of the reference (MCH 10⁻⁶M)    -   2nd measurement: pKB value

Reagents: HBSS (10×) (GIBCO) HEPES buffer (1 M) (GIBCO) Pluronic F-127(Molecular Probes) Fluo-4 (Molecular Probes) Probenecid (Sigma) MCH(Bachem) bovine serum albumin (Serva) (protease-free) DMSO (Serva) Ham'sF12 (BioWhittaker) FCS (BioWhittaker) L-Glutamine (GIBCO) Hygromycin B(GIBCO) PENStrep (BioWhittaker) Zeocin (Invitrogen)

Clonal CHO/Galpha16 hMCH-R1 cells are cultivated in Ham's F12 cellculture medium (with L-glutamine; BioWhittaker; Cat.No.: BE12-615F).This contains per 500 ml 10% FCS, 1% PENStrep, 5 ml L-glutamine (200 mMstock solution), 3 ml hygromycin B (50 mg/ml in PBS) and 1.25 ml zeocin(100 μg/ml stock solution). One day before the experiment the cells areplated on a 384-well microtitre plate (black-walled with a transparentbase, made by Costar) in a density of 2500 cells per cavity andcultivated in the above medium overnight at 37° C., 5% CO₂ and 95%relative humidity. On the day of the experiment the cells are incubatedwith cell culture medium to which 2 mM Fluo-4 and 4.6 mM Probenicid havebeen added, at 37° C. for 45 minutes. After charging with fluorescentdye the cells are washed four times with Hanks buffer solution (1×HBSS,20 mM HEPES), which is combined with 0.07% Probenicid. The testsubstances are diluted in Hanks buffer solution, combined with 2.5%DMSO. The background fluorescence of non-stimulated cells is measured inthe presence of substance in the 384-well microtitre plate five minutesafter the last washing step in the FLIPR³⁸⁴ apparatus (MolecularDevices; excitation wavelength: 488 nm; emission wavelength: bandpass510 to 570 nm). To stimulate the cells MCH is diluted in Hanks bufferwith 0.1% BSA, pipetted into the 384-well cell culture plate 35 minutesafter the last washing step and the MCH-stimulated fluorescence is thenmeasured in the FLIPR³⁸⁴ apparatus.

Data Analysis:

1st measurement: The cellular Ca²⁺ mobilisation is measured as the peakof the relative fluorescence minus the background and is expressed asthe percentage of the maximum signal of the reference (MCH 10⁻⁶M). Thismeasurement serves to identify any possible agonistic effect of a testsubstance.

2nd measurement: The cellular Ca²⁺ mobilisation is measured as the peakof the relative fluorescence minus the background and is expressed asthe percentage of the maximum signal of the reference (MCH 10⁻⁶M, signalis standardised to 100%). The EC50 values of the MCH dosage activitycurve with and without test substance (defined concentration) aredetermined graphically by the GraphPad Prism 2.01 curve program. MCHantagonists cause the MCH stimulation curve to shift to the right in thegraph plotted.

The inhibition is expressed as a pKB value:pKB=log(EC _(50(testsubstance+MCH))/EC_(50(MCH))−1)−log c_((testsubstance))

The compounds according to the invention, including their salts, exhibitan MCH-receptor antagonistic activity in the tests mentioned above.Using the MCH-1 receptor binding test described above an antagonisticactivity is obtained in a dosage range from about 10⁻¹⁰ to 10⁻⁵ M,particularly from 10⁻⁹ to 10⁻⁶ M. The following IC50 values weredetermined using the MCH-1 receptor binding test described above:

Compound according to Example No. Name of substance IC50 value 1.85-(4-bromo-phenyl)-2-[4-(2-pyrrolidin-1-yl-  8 nMethoxy)-phenylethynyl]-pyridine 1.3(2-{4-[5-(3,4-difluorophenyl)-pyridin-2- 74 nMylethynyl]-phenoxy}-ethyl)-diethyl-amine

Some examples of formulations will be described hereinafter, wherein theterm “active substance” denotes one or more compounds according to theinvention, including their salts. In the case of one of the combinationswith one or more active substances described, the term “activesubstance” also includes the additional active substances.

EXAMPLE A Capsules for Powder Inhalation Containing 1 mg ActiveSubstance

Composition: 1 capsule for powder inhalation contains: active substance 1.0 mg lactose 20.0 mg hard gelatine capsules 50.0 mg 71.0 mgMethod of Preparation:

The active substance is ground to the particle size required forinhalation. The ground active substance is homogeneously mixed with thelactose. The mixture is packed into hard gelatine capsules.

EXAMPLE B Inhalable Solution for Respimat® Containing 1 mg activeSubstance

Composition: 1 spray contains: active substance 1.0 mg benzalkoniumchloride 0.002 mg disodium edetate 0.0075 mg purified water ad 15.0 μlMethod of Preparation:

The active substance and benzalkonium chloride are dissolved in waterand packed into Respimat® cartridges.

EXAMPLE C Inhalable Solution for Nebulisers Containing 1 mg ActiveSubstance

Composition: 1 vial contains: active substance 0.1 g sodium chloride0.18 g benzalkonium chloride 0.002 g purified water ad 20.0 mlMethod of Preparation:

The active substance, sodium chloride and benzalkonium chloride aredissolved in water.

EXAMPLE D Propellant Type Metered Dose Aerosol Containing 1 mg ActiveSubstance

Composition: 1 spray contains: active substance  1.0 mg lecithin  0.1%propellant gas ad 50.0 μlMethod of Preparation:

The micronised active substance is homogeneously suspended in themixture of lecithin and propellant gas. The suspension is transferredinto a pressurised contained with a metering valve.

EXAMPLE E Nasal Spray Containing 1 mg Active Substance

Composition: active substance 1.0 mg sodium chloride 0.9 mg benzalkoniumchloride 0.025 mg disodium edetate 0.05 mg purified water ad 0.1 mlMethod of Preparation:

The active substance and the excipients are dissolved in water andtransferred into a corresponding container.

EXAMPLE F Injectable Solution Containing 5 mg of Active Substance Per 5ml

Composition: active substance 5 mg glucose 250 mg human serum albumin 10mg glycofurol 250 mg water for injections ad 5 mlPreparation:

Glycofurol and glucose are dissolved in water for injections (Wfl);human serum albumin is added; active ingredient is dissolved withheating; made up to specified volume with Wfl; transferred into ampoulesunder nitrogen gas.

EXAMPLE G Injectable Solution Containing 100 mg of Active Substance Per20 ml

Composition: active substance 100 mg monopotassium dihydrogen phosphate= KH₂PO₄ 12 mg disodium hydrogen phosphate = Na₂HPO₄.2H₂O 2 mg sodiumchloride 180 mg human serum albumin 50 mg Polysorbate 80 20 mg water forinjections ad 20 mlPreparation:

Polysorbate 80, sodium chloride, monopotassium dihydrogen phosphate anddisodium hydrogen phosphate are dissolved in water for injections (Wfl);human serum albumin is added; active ingredient is dissolved withheating; made up to specified volume with Wfl; transferred intoampoules.

EXAMPLE H Lyophilisate Containing 10 mg of Active Substance

Composition: Active substance 10 mg Mannitol 300 mg human serum albumin20 mgPreparation:

Mannitol is dissolved in water for injections (Wfl); human serum albuminis added; active ingredient is dissolved with heating; made up tospecified volume with Wfl; transferred into vials; freeze-dried.

Solvent for lyophilisate: Polysorbate 80 = Tween 80 20 mg mannitol 200mg water for injections ad 10 mlPreparation:

Polysorbate 80 and mannitol are dissolved in water for injections (Wfl);transferred into ampoules.

EXAMPLE I Tablets Containing 20 mg of Active Substance

Composition: active substance  20 mg lactose 120 mg maize starch  40 mgmagnesium stearate  2 mg Povidone K 25  18 mgPreparation:

Active substance, lactose and maize starch are homogeneously mixed;granulated with an aqueous solution of Povidone; mixed with magnesiumstearate; compressed in a tablet press; weight of tablet 200 mg.

EXAMPLE J Capsules Containing 20 mg Active Substance

Composition: active substance  20 mg maize starch  80 mg highlydispersed silica   5 mg magnesium stearate 2.5 mgPreparation:

Active substance, maize starch and silica are homogeneously mixed; mixedwith magnesium stearate; the mixture is packed into size 3 hard gelatinecapsules in a capsule filling machine.

EXAMPLE K Suppositories Containing 50 mg of Active Substance

Composition: active substance  50 mg hard fat (Adeps solidus) q.s. ad1700 mgPreparation:

Hard fat is melted at about 38° C.; ground active substance ishomogeneously dispersed in the molten hard fat; after cooling to about35° C. it is poured into chilled moulds.

EXAMPLE L Injectable Solution Containing 10 mg of Active Substance Per 1ml

Composition: active substance 10 mg mannitol 50 mg human serum albumin10 mg water for injections ad 1 mlPreparation:

Mannitol is dissolved in water for injections (Wfl); human serum albuminis added; active ingredient is dissolved with heating; made up tospecified volume with Wfl; transferred into ampoules under nitrogen gas.

1. An alkyne compound of formula IIa:

wherein R¹ and R² together form an alkylene bridge in such a way thatR¹R²N— denotes a pyrrolidine group, wherein one or more H atoms areoptionally replaced by R¹⁴, X is —CH₂—CH₂—O— or —CH₂—CH₂—NR⁴—, whereinone or two C atoms in each case are optionally substituted with one ortwo identical or different substituents selected from C₁₋₆-alkyl, Z is asingle bond, R⁴ is H or C₁₋₄-alkyl, R¹⁴ denotes C₁₋₄-alkyl,C₂₋₄-alkenyl, C₂₋₄-alkynyl, C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₃-alkyl,hydroxy, ω-hydroxy-C₁₋₃-alkyl, C₁₋₄-alkoxy, ω-(C₁₋₄-alkoxy)-C₁₋₃-alkyl,C₁₋₄-alkyl-carbonyl, carboxy, C₁₋₄-alkoxycarbonyl,hydroxy-carbonyl-C₁₋₃-alkyl, C₁₋₄-alkoxycarbonyl-C₁₋₃-alkyl,C₁₋₄-alkoxy-carbonylamino, C₁₋₄-alkoxy-carbonylamino-C₁₋₃-alkyl, amino,C₁₋₄-alkyl-amino, C₃₋₇-cycloalkyl-amino,N-(C₃₋₇-cycloalkyl)-N-(C₁₋₄-alkyl)-amino, di-(C₁₋₄-alkyl)-amino,amino-C₁₋₃-alkyl, C₁₋₄-alkyl-amino-C₁₋₃-alkyl,C₃₋₇-cycloalkyl-amino-C₁₋₃-alkyl,N-(C₃₋₇-cycloalkyl)-N-(C₁₋₄-alkyl)-amino-C₁₋₃-alkyl,di-(C₁₋₄-alkyl-amino-C₁₋₃-alkyl, cyclo-C₃₋₆-alkyleneimino-C₁₋₃-alkyl,aminocarbonyl, C₁₋₄-alkyl-amino-carbonyl,C₃₋₇-cycloalkyl-amino-carbonyl,N-(C₃₋₇-cycloalkyl)-N-(C₁₋₄-alkyl)-amino-carbonyl,di-(C₁₋₄-alkyl)-amino-carbonyl, Q is CH, L¹, L², and L³, independentlyof one another are F, Cl, Br, I, OH, cyano, C₁₋₄-alkyl, C₂₋₄-alkynyl,C₁₋₄-alkoxy, difluoromethyl, trifluoromethyl, amino, C₁₋₄-alkylamino,di-(C₁₋₄-alkyl)-amino, acetylamino, aminocarbonyl, difluoromethoxy,trifluoromethoxy, amino-C₁₋₃-alkyl, C₁₋₄-alkylamino-C₁₋₃-alkyl ordi-(C₁₋₄-alkyl)-amino-C₁₋₃-alkyl or nitro, with the proviso that aphenyl may only be monosubstituted by nitro, m, n, and p, independentlyof one another represent the values 0, 1 or 2, and p may also have thevalue 3, while in the above-mentioned groups X, R¹, R², R⁴ and R¹⁴ oneor more C atoms are optionally additionally mono- or polysubstituted byF and/or one or two C atoms, independently of one another, areoptionally additionally monosubstituted by Cl or Br, or a tautomer, adiastereomer, an enantiomer, a mixture thereof or a salt thereof.
 2. Analkyne compound according to claim 1, which is in a physiologicallyacceptable salt form.
 3. A composition comprising an alkyne compoundaccording to claim 1, together with one or more inert carriers and/ordiluents.
 4. A method for influencing the eating behavior of a mammal toreduce body weight or prevent an increase in the body weight comprisingadministering thereto an effective amount of one or more alkynecompounds according to claim
 1. 5. A method for treating a urinaryproblem selected from the group consisting of urinary incontinence,overactive bladder, urgency, nycturia and enuresis, in a mammalcomprising administering thereto an effective amount of one or morealkyne compounds according to claim
 1. 6. An alkyne compound of claim 1wherein R⁴ is —H, methyl, ethyl or propyl.
 7. An alkyne compoundaccording to claim 1, wherein X is —CH₂—CH₂—O—.
 8. An alkyne compoundaccording to claim 1, wherein R¹⁴ is C₁₋₄-alkyl, hydroxy,ω-hydroxy-C₁₋₃-alkyl, C₁₋₄-alkoxy and ω-(C₁₋₄-alkoxy)-C₁₋₃-alkyl.
 9. Analkyne compound according to claim 1, wherein L¹, L² and L³independently of each other denote F, Cl, Br, I, OH, cyano, methyl,difluoromethyl, trifluoromethyl, ethyl, n-propyl, iso-propyl, methoxy,difluoromethoxy, trifluoromethoxy, ethoxy, n-propoxy or iso-propoxy,while any substituents L¹, L² and L³ occurring repeatedly may haveidentical or different meanings.
 10. An alkyne compound according toclaim 1, selected from the following formulae: (1)[(R)-1-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-ethyl)-pyrrolidin-2-yl]-methanol;(2)5-(4-chloro-phenyl)-2-[3-methyl-4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridine;(3)[(S)-1-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxy}-ethyl)-pyrrolidin-2-yl]-methanol;(4)5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-(2-pyrrolidin-1-yl-ethoxy)-phenylamine;(5)2-[3-bromo-4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-5-(4-chloro-phenyl)-pyridine;(6){4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-(2-pyrrolidin-1-yl-ethyl)-amine;(7) tert-butyl[1-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-ethyl)-pyrrolidin-3-yl]-carbaminate;(8)5-(4-chloro-phenyl)-2-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridine;(9)5-(4-chloro-phenyl)-2-[3-chloro-4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridine;(10)(S)-1-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxy}-ethyl)-pyrrolidin-3-ol,(11)5-(4-bromo-phenyl)-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridine;(12)5-(4-chloro-phenyl)-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridine;(13)5-(4-chloro-phenyl)-2-{4-]2-(2-methyl-pyrrolidin-1-yl)-ethoxy]-phenylethynyl}-pyridine;(14)(R)-1-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxy}-ethyl)-pyrrolidin-3-ol;(15)5-(4-chloro-phenyl)-2-[3-ethynyl-4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridine;(16)[1-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxy}-ethyl)-pyrrolidin-3-yl]-dimethyl-amine;and (17)5-(4-chloro-phenyl)-2[3-fluoro-4-(2-pyrrolodin-1-yl-ethoxy)-phenylethynyl]-pyridine;or an enantiomer; a mixture thereof or a salt thereof.
 11. An alkynecompound, which compound is[(R)-1-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-ethyl)-pyrrolidin-2-yl]-methanolor an enantiomer, a mixture thereof or a salt thereof.
 12. An alkynecompound, which compound is[(S)-1-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxy}-ethyl)-pyrrolidin-2-yl]-methanolor an enantiomer, a mixture thereof or a salt thereof.
 13. An alkynecompound, which compound is 5-(4-chloro-phenyl)-2- [3-methoxy-4-(2-pyrrolidin- 1-yl-ethoxy)-phenylethynyl]-pyridine or a mixture thereofor a salt thereof.
 14. An alkyne compound, which compound is(S)-1-(2-{4-[5-(4- chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxy}-ethyl)-pyrrolidin-3-ol or anenantiomer, a mixture thereof or a salt thereof.
 15. An alkyne compound,which compound is5-(4-bromo-phenyl)-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridineor a mixture thereof or a salt thereof.
 16. An alkyne compound, whichcompound is5-(4-chloro-phenyl)-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridineor a mixture thereof or a salt thereof.
 17. An alkyne compound, whichcompound is [1-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxy}-ethyl)-pyrrolidin-3-yl]-dimethyl-amine ora mixture thereof or a salt thereof.